Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes

ABSTRACT

The present invention provides a preventive or therapeutic agent of a new type for diabetes mellitus and diabetic complications on the basis of an adenosine A2 receptor antagonist action. 
     A purine compound represented by the formula (I), its pharmacologically acceptable salt or hydrates thereof has an adenosine A2 receptor antagonistic action and is useful for prevention or therapy of diabetes mellitus and diabetic complications. In addition, adenosine A2 receptor antagonists having different structures from those of the compounds described above, for example KW6002, are also effective for prevention or therapy of diabetes mellitus and diabetic complications. 
                 
 
     In the formula, W is —CH 2 CH 2 —, or —CH═CH— or —C≡C—; R 1  is: 
                 
 
(in the formula, X is hydrogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group, etc.; and R 5  and R 6  are the same as or different from each other and each represents hydrogen atom, a lower alkyl group, a cycloalkyl group, etc.) and the like; R 2  is an amino group, etc. which maybe substituted with a lower alkyl group, etc.; R 3  is a cycloalkyl group, an optionally substituted aryl group, etc.; and R 4  is a lower alkyl group etc.

This application is the national phase under 35 U.S.C. §371 or PCTInternational Application No. PCT/JP98/05870 which has an Internationalfiling date of Dec. 24, 1998, which is designated the United States ofAmerica.

TECHNICAL FIELD TO WHICH THE INVENTION BELONGS

The present invention relates to a novel purine compound having anadenosine receptor antagonism and to a preventive or therapeutic agentfor diabetes mellitus and diabetic complication comprising an adenosinereceptor antagonist having a hypoglycemic action and a glucose toleranceimproving action on the basis of an inhibiting action to saccharogenesisglucose production and a promoting action to saccharide glucoseutilization at the periphery. More particularly, it relates to apreventive or therapeutic agent for diabetes mellitus and diabeticcomplications in which an adenosine receptor antagonist is an adenosineA2 receptor antagonist.

PRIOR ART

With regard to therapeutic agents for diabetes mellitus, variousbiguanide compounds and sulfonylurea compounds have been used. However,the biguanide compounds induce a lactic acidosis and, therefore, theiruse is limited while the sulfonylurea compounds often result in a severehypoglycemia due to their strong hypoglycemic action and, therefore,their use is to be careful.

An object of the present invention is to provide a preventive ortherapeutic agent for diabetes mellitus and diabetic complications onthe basis of a new action mechanism which is different from that ofconventional biguanide compounds and sulfonylurea compounds havingseveral limitations in actual use.

DISCLOSURE OF THE INVENTION

The present inventors have carried out various investigations and, as aresult, they have found that antagonists to adenosine receptors can bepreventive or therapeutic agents of a new type for diabetes mellitus.Thus, hyperglycemia of spontaneous diabetic mice was relieved by anadenosine receptor antagonist. Such an action is presumed to be theresults of inhibition of the gluconeogenic action and the glycogenolyticaction, promoted by endogenous adenosine, from liver by an antagonist.Based upon such a finding, the present inventors have carried out aninvestigation for the compounds having excellent hypoglycemic action andglucose tolerance improving action as a preventive or therapeutic agentand have found novel purine compounds represented by the followingformula (I). As a result of further investigation of their actionmechanism in detail, they have found that, among the adenosine receptorantagonistic action, the adenosine A2 receptor antagonistic action isthe real substance for showing the hypoglycemic and glucose toleranceimproving action and have accomplished the present invention whereadenosine A2 receptor antagonist is a preventive or therapeutic agent ofa new type for diabetes and diabetic complications.

The novel purine compound according to the present invention isrepresented by the following formula (I).

A purine compound represented by the formula (I), its pharmacologicallyacceptable salt or hydrates thereof.

In the formula R¹ means:

-   -   1) formula:    -    (in the formula, X represents hydrogen atom, hydroxyl group, an        optionally substituted lower alkyl group, an optionally        substituted lower alkoxy group, an optionally substituted aryl        group, an optionally substituted heteoaryl group, an optionally        substituted acyl group, an optionally substituted acyloxy group        or an optionally substituted amino group; and R⁵ and R⁶ are the        same as or different from each other and each represents        hydrogen atom, an optionally substituted lower alkyl group, an        optionally substituted saturated or unsaturated C₃₋₈ cycloalkyl        group, an optionally substituted C₃₋₈cycloalkyl-C₂₋₆alkyl group,        an optionally substituted aryl group, an optionally substituted        heteroaryl group, an optionally protected carboxyl group or an        optionally substituted four to six membered ring having at least        one hetero atom. Alternatively, R⁵ and R⁶ may represent an        oxygen atom or a sulfur atom together or may represent a ring        being formed together with the carbon atom to which they are        bonded which may have a hetero atom. This ring may be        substituted.); or    -   2) a five- or six-membered aromatic ring which may have        substituent group and hetero atom.

W represents a formula —CH₂CH₂—, —CH═CH— or —C≡C—.

R² represents hydrogen atom, an optionally substituted lower alkylgroup, hydroxyl group or a formula —NR⁷R⁸ (in which R⁷ and R⁸ are thesame as or different from each other and each represents hydrogen atom,hydroxyl group, an optionally substituted lower alkyl group, anoptionally substituted acyl group, an optionally substituted C₃₋₈cycloalkyl group, an optionally substituted aryl group or an optionallysubstituted heteroaryl group. Alternatively, R⁷and R⁸ may be a saturatedring which is formed together with a nitrogen atom to which they arebonded. This ring may further have a hetero atom or a substituent).

R³ represents hydrogen atom, an optionally substituted C₃₋₈ cycloalkylgroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group or an optionally substituted C₂₋₆ alkenyl group.

R⁴ represents hydrogen atom, an optionally substituted lower alkylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group or an optionally substituted cyclic ether.

However, the case where (1) W is —CH₂CH— and X is hydrogen atom and analkyl group or where (2) W is —C≡C—, R³ is hydrogen atom and R⁴ is anoptionally substituted cyclic ether is excluded.

There has been no report that an adenosine A2 receptor antagonist iseffective for prevention and therapy of diabetes mellitus and diabeticcomplications.

The present invention provides a preventive or therapeutic agent fordiabetes, a preventive or therapeutic agent for diabetic complications,a hypoglycemic agent, an improving agent for impaired glucose tolerance,a potentiating agent for insulin sensitivity obesity which comprises apurine compound of the formula (I), its pharmacologically acceptablesalt or hydrates thereof as an active ingredient.

The present invention provides a method or a use by administering apharmacologically or clinically effective amount of purine compound ofthe formula (I), its pharmacologically acceptable salt or hydratesthereof to a patient for prevention or therapy of diabetes mellitus, forprevention or therapy of diabetic complications, for prevention ortherapy of a disease against which a purine compound of the formula (I),its pharmacologically acceptable salt or hydrates thereof is effectivefor its prevention or therapy, for hypoglycemia, for improvement ofimpaired glucose tolerance, for potentiation of insulin sensitivity, offor prevention and therapy of obesity.

The present invention provides a pharmaceutical composition containing apharmacologically or clinically effective amount of a purine compound ofthe formula (I), its pharmacologically acceptable salt or hydratesthereof.

Adenosine is a nucleoside widely existing in living body and has aphysiological action to a cardiovascular system, a central nervoussystem, a respiratory system, kidney, an immune system, etc. The actionof adenosine is achieved via at least four receptors—A1, A2a, A2b andA3—in which G protein is participated (Fredholm, B. B. et al.,Pharmacol. Rev., 46, 143-156, 1994.). In 1979, adenosine receptor was atfirst classified into A1 and A2 on the basis of their pharmacologicalaction and participation in adenylate cyclase (Van Calker, D. et al., J.Neurochem., 33, 999-1003, 1979.). Then A2 receptor has classified intothe subtypes of A2a and A2b on the basis of high and low affinity toadenosine and to adenosine A2 agonists, i.e. NECA and CGS-21680 (Burns,R. F. et al., Mol. Pharmacol., 29, 331-346, 1986.; Wan, W. et al., J.Neurochem., 55, 1763-1771, 1990.). Although gradually, physiological andpathological significance of those receptors has been clarified in acentral nervous system, a circulatory system, etc.

With regard to saccharometabolism, glucose metabolism, the followingreports have been available. In an experiment using skeletal muscles,adenosine lowers the insulin sensitivity due to an agonistic action tothe A1 receptor suppressing the incorporation of saccharide glucoseuptake while an A1 receptor antagonist increases the insulin sensitivity(Challis, R. A., Biochem. J., 221, 915-917, 1984; Challis, R. A. , Eur.J. Pharmacol. 226, 121-128, 1992.). In fat cells, adenosine enhances thesensitivity of insulin via an A1 receptor, whereby incorporation ofsaccharide glucose uptake is promoted (Vannucci, S. J., et al., Biochem.J., 228, 325-330, 1992). Further WO 95/18128 and WO 98/03507 disclose atherapeutic agent for diabetes mellitus comprising an A1 receptorantagonist. This, there have been many reports concerning an A1receptor. With regard to an adenosine A2 receptor, there is a simpledescription in WO 97/01551 suggesting a therapeutic agent for diabetesmellitus comprising the A2a receptor antagonist although any grouptherefor is not mentioned at all. In Collis, M. G. et al., TrendsPharmacol. Sci., 14, 360-366, 1993., participation of the adenosine A2receptor in the promotion of gluconeogenesis in hepatic cells issuggested but there is no specific description at all. On the contrary,WO 98/01459 describes a therapeutic agent for diabetes mellituscomprising the A2 receptor agonist but thee is no description for theadenosine A2 receptor antagonist at all. As such, the positioning of theadenosine A2 receptor antagonist as a therapeutic agent for diabetesmellitus has been in a chaotic state.

The adenosine A2 receptor antagonist of the present invention as apreventive or therapeutic agent for diabetes mellitus and for diabeticcomplications is selected, for example, from the following compounds 1)to 4).1) Formula (I)

In the formula R¹ represents:

-   -   (1) formula:    -    (in the formula X is hydrogen atom, hydroxyl group, an        optionally substituted lower alkyl group, an optionally        substituted lower alkoxy group, an optionally substituted aryl        group, an optionally substituted heteroaryl group, an optionally        substituted acyl group, an optionally substituted acyloxy group        or an optionally substituted amino group; and R⁵ and R⁶ are the        same as or different from each other and each represents        hydrogen atom, an optionally substituted lower alkyl group, an        optionally substituted saturated or unsaturated C₃₋₈ cycloalkyl        group, an optionally substituted C₃₋₈ cycloalkyl-C₂₋₆ alkyl        group, an optionally substituted aryl group, an optionally        substituted heteroaryl group, an optionally protected carboxyl        group or an optionally substituted four- to six-membered ring        having at least one hetero atom. Alternatively, R⁵ and R⁶        represents an oxygen atom or a sulfur atom together or        represents a ring which may have hetero atom being formed        together with the carbon atom to which they are bonded. This        ring may be substituted); or    -   (2) a five- or six-membered aromatic ring which may have        substituent group and hetero atom.

W represents formula —CH₂CH₂—, —CH═CH—, or —C≡C—.

R² represents hydrogen atom, an optionally substituted lower alkylgroup, hydroxyl group or a formula —NR⁷R⁸ (in which R⁷ and R⁸ are thesame as or different from each other and each represents hydrogen atom,a hydroxyl group, an optionally substituted lower alkyl group, anoptionally substituted acyl group, an optionally substituted C₃₋₈cycloalkyl group, an optionally substituted aryl group or an optionallysubstituted heteoaryl group. Alternatively, R⁷ and R⁸ represents asaturated ring which is formed together with a nitrogen atom to whichthey are bonded. This ring may further have hetero atom or substituent.)

R³ represents hydrogen atom, an optionally substituted C₃₋₈ cycloalkylgroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group or an optionally substituted C₂₋₆ alkenyl group.

R⁴ represents hydrogen atom, an optionally substituted lower alkylgroup, an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group or an optionally substituted cyclic ether group.

However, the case where (1) W is —CH₂CH₂— and X is hydrogen atom and analkyl group or where (2) W is —C≡C—, R³ is hydrogen atom and R⁴ is anoptionally substituted cyclic ether is excluded.

That is, the present invention is the purine compound of the aboveformula (I), its pharmacologically acceptable salt or hydrates thereof.

Among these compounds, the preferred examples are those where W isethylene group or ethylene group and the more preferred example is thatwhere W is ethynylene group.

The purine compound of the present invention includes anethynylenepurine compound represented by the formula (I′):

except the case where R³ is hydrogen atom and R⁴ is an optionallysubstituted cyclic ether.2) A compound represented by the formula (VII):

(in the formula, R^(1α) and R^(2α) are the same as or different fromeach other and each represents a C₁₋₄ lower alkyl group or allyl group;R^(3α) represents hydrogen atom or a C₁₋₃ lower alkyl group; and R^(4α),R^(5α), R^(6α) and R^(7α) are the same as or different from each otherand each represents hydrogen atom, a halogen atom, a C₁₋₃ lower alkylgroup, a C₁₋₃ lower alkoxy group, nitro group, amino group or hydroxylgroup) or a pharmaceutically acceptable salt thereof.

Among those compounds, the preferred examples are those where R^(1α),R^(2α) and R^(3α) are the same as or different from each other and eachrepresents a C₁₋₃ lower alkyl group and any of R^(4α), R^(5α), R^(6α)and R^(7α) is a C₁₋₃ lower alkoxy group, and the more preferred examplesare those where R^(1α), R^(2α) and R^(3α) are the same as or differentfrom each other and each represents a C₁₋₃ lower alkyl group and R^(5α)and R^(6α) are methoxy groups.3) A compound represented by the formula (VII):

(in the formula, E represents an oxygen atom, a sulfur atom, SO₂ or NH;F represents a C₅₋₆ cycloalkyl group, a pyridyl group, a thizolyl group,a C₁₋₆ alkyl group, an optionally substituted phenyl group, anoptionally substituted phenyl-C₁₋₂ alkyl group, a morphoinoethyl group,a furylmethyl group or a pyridylmethyl group; and G represents a furylgroup, a thienyl group or an isoxazolyl group) or a pharmacologicallyacceptable salt thereof.

Among those compounds, the preferred examples are those where E is NH, Fis 2-(4-hydroxyphenyl)ethyl group or 2-(morpholino)ethyl group and G isa furyl group.4) A compound represented by the formula (IX):

(in the formula, the ring M represents pyrazole or triazole; and Prepresents a phenyl-(C₁₋₃)alkyl group optionally substituted withhalogen atom, an alkyl group, an alkoxy group or cyano, or a C₁₋₆ alkylgroup) or a pharmacologically acceptable salt thereof.

Among those compounds, the preferred example is that where the ring M ispyrazole and P is a phenethyl group.5) A compound represented by the formula (X):

(in the formula, U represents an oxygen atom, a sulfur atom or NH group;V represents an optionally hydroxyl-substituted lower alkyl group, aphenyl or aralkyl group which may be substituted with a lower alkoxygroup, a lower alkyl group, a halogen atom, hydroxyl group, etc. or aheteroaryl group; Z₁ represents hydrogen atom, a halogen atom or a loweralkyl group; and Z₂ represents a heteroaryl group such as a furyl group)or a pharmaceutically acceptable salt thereof.

Among those compounds, the preferred one is that where U is an oxygenatom, V is 2,6-dimethoxyphenyl group, Z₁ is hydrogen atom and Z₂ is afuryl group.

The present invention provides a preventive or therapeutic agent fordiabetes, a preventive or therapeutic agent for diabetic complications,a hypoglycemic agent, an improving agent for impaired glucose tolerance,a potentiating agent for insulin sensitivity or obesity which comprisesan adenosine A2 receptor antagonist, its pharmacologically acceptablesalt or hydrates thereof as an active ingredient.

It is preferred that the above adenosine A2 receptor antagonist itsadenosine A2a and/or A2b receptor antagonist.

Examples of those which are preferred as the adenosine A2a or A2breceptor antagonist of the present invention are those where the Kivalue showing an affinity to the A2a receptor by the experimental methodwhich will be mentioned later is not more than 0.5 μM, those where theIC₅₀ value showing the suppression of cAMP production stimulated by NECAin the A2b receptor is not more than 0.7 μM or those satisfying both ofthem. Examples of those which are more preferred are those where the Kivalue showing an affinity to the A2a receptor by the experimental methodwhich will be mentioned later is not more than 0.1 μM, those where theIC₅₀ value showing the suppression of cAMP production stimulated by NECAin the A2b receptor is not more than 0.5 μM or those satisfying both ofthem.

The present invention provides a method or a use by administrating apharmacologically or clinically effective amount of an adenosine A2receptor antagonist, its pharmacologically acceptable salt or hydratesthereof to a patient for prevention of therapy of diabetes mellitus, forprevention or therapy of diabetic complications, for prevention ortherapy of a disease against which an adenosine A2 receptor antagonist,its pharmacologically acceptable salt or hydrates thereof is effectivefor its prevention or therapy, for hypoglycemia, for improvement ofimpaired glucose tolerance, for potentiation of insulin sensitivity, orfor prevention and therapy of obesity.

The present invention provides a pharmaceutical composition containing apharmacologically or clinically effective amount of an adenosine A2receptor antagonist, its pharmacologically acceptable salt or hydratesthereof.

In the formula (I), the term “optionally substituted” used in anoptionally substituted lower alkyl group, an optionally substitutedlower alkoxy group, an optionally substituted cycloalkyl group, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, etc. in the definitions for X, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸represents that each of the groups may be substituted with a groupselected, for example, from a hydroxyl group; a thiol group; a nitrogroup; a cyano group; a halogen atom such as a fluorine atom, a chlorineatom, a bromine atom and an iodine atom; a lower alkyl group such asmethyl, ethyl, n-propyl and isopropyl; a lower alkoxy group such asmethoxy, ethoxy, n-propoxy, isopropoxy and butoxy groups; a halogenatedalkyl group such as a fluoromethyl group, a difluoromethyl group, atrifluoromethyl group and a 2,2,2-trifluoroethyl group; an alkylthiogroup such as methylthio group, an ethylthio group and an isopropylthiogroup; an acyl group such as an acetyl group, a propionyl group and abenzoyl group; a hydroxyalkyl group such as a hydroxymethyl group, ahydroxyethyl group and a hydroxypropyl group; an amino group; amonoalkylamino group such as a methylamino group, an ethylamino groupand an isopropylamino group; a dialkylamino group such as adimethylamino group and a diethylamino group; a cyclic amino group suchas an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, apiperidinyl group, a perhydroazepinyl group and a piperazinyl group; acarboxyl group; an alkoxycarbonyl group such as a methoxycarbonyl group,an ethoxycarbonyl group and a propylcarbonyl group; a carbamoyl group;an alkylcarbamoyl group such as a methylcarbamoyl group and adimethylcarbamoyl group; an acylamino group such as an acetylamino groupand a benzoylamino group; an unsubstituted or C₁₋₄ alkyl-substitutedsulfamoyl group or an alkylsulfonyl group such as a methylsulfonyl groupand an ethylsulfonyl group; an unsubstituted or substituted arylsulfonylgroup such as a benzenesulfonyl group and a p-toluenesulfonyl group; anunsubstituted or substituted aryl group such as a phenyl group, a tolylgroup and an anisolyl group, as unsubstituted or substituted heteroarylgroup such as a pyrrole group, a pyrazolyl group, an imidazolyl group, atriazolyl group, a tetrazolyl group, a thiazolyl group, a pyridyl group,a pyrimidyl group and a pyrazinyl group; a carboxyalkyl group; analkyloxycarbonylalkyl group such as a methoxycarbonylmethyl group, anethoxycarbonylmethyl group and a methoxycarbonylethyl group; acarboxyalkoxy group such as a carboxymethoxy group; an arylalkyl groupsuch as a benzyl group and a 4-chlorobenzyl group; a heteroarylalkylgroup such as a pyridylmethyl group and a pyridylethyl group; analkylenedioxy group such as a methylenedioxy group and an ethylenedioxygroup; etc.

The halogen atom in the definitions for A and B is fluorine, chlorine,bromine or iodine.

The lower alkyl group in the definitions for X, R², R⁴, R⁵, R⁶, R⁷ andR⁸ means a linear or branched alkyl group having 1-6 carbon atoms. Itsexamples are methyl group, ethyl group, n-propyl group, isopropyl group,n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, 1,2-dimethylpropyl group, 1,1-dimethylpropyl group,2,2-dimethylpropyl group, 2-ethylpropyl group, n-hexyl group,1,2-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutylgroup, 1-ethyl-2-methylpropyl group and 1-methyl-2-ethylpropyl group.

The lower alkoxy group in the definitions for X means a linear orbranched alkoxy group having 1-6 carbon atoms. Its examples are methoxygroup, ethoxy group, n-propoxy group, isopropoxy group, a n-butoxygroup, sec-butoxy group, tert-butoxy group, n-pentyloxy group,1,2-dimethylpropyloxy group, 1,1-dimethylpropyloxy group,2,2-dimethylpropyloxy group, 2-ethylpropyloxy group, n-hexyloxy group,1,2-dimethylbutyloxy group, 2,3-dimethylbutyloxy group,1,3-dimethylbutyloxy group, 1-ethyl-2-methylpropyloxy group and1-methyl-2-ethylpropyloxy group.

The cycloalkyl group in the definitions for X, R³, R⁴, R⁵, R⁶, R⁷ and R⁸means a cycloalkyl group having 3-8carbons such as cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl groupor cyclooctyl group.

The cycloalkylalkyl group in the definitions for X, R³, R⁴, R⁵, R⁶, R⁷and R⁸ means a group where the above cycloalkyl group is bonded to anyof the carbon atoms in the above lower alkyl group.

The lower alkenyl group in the definitions for R³ and R⁴ means a linearor branched alkenyl group having 2-6 carbon atoms such as vinyl group,1-propenyl group, 2-propenyl group, isopropenyl group,2-methyl-1-propenyl group, 3-methyl-1-propenyl group,2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group,2-butenyl group and 3-butenyl group.

The lower alkynyl group in the definition for R⁴ represents a linear orbranched alkynyl group having 2-6 carbon atoms such as ethynyl group,1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group,3-butynyl group, 3-methyl-1-propynyl group and 2-methyl-3-propynylgroup.

The acyl group in the definitions for X and R² represents is groupdefined from an aliphatic saturated monocarboxylic acid such as acetylgroup, propionyl group, butyryl group, valeryl group, isovaleryl groupand pivaloyl group; a group derived from an aliphatic unsaturatedcarboxylic acid such as acryloyl group, propioloyl group, methacrylolylgroup, crotonoyl group and isocrotonoyl group; a group derived from acarbocyclic carboxylic acid such as benzoyl group, naphthoyl group,toluoyl group, hydroatropoyl group, atropoyl group and cinnamoyl group;a group derived from a heterocyclic carboxylic acid such as furoylgroup, thenoyl group, nicotinoyl group and isonicotinoyl group; a groupderived from a hydroxycarboxylic acid or an alkoxycarboxylic acid suchas glycoloyl group, lactoyl group, glyceroyl group, tropoyl group,benzyloyl group, salicyloyl group, anisoyl group, vanilloyl group,piperoniloyl group and galloyl group; a group derived from various kindsof amino acids; etc.

The aryl group in the optionally substituted aryl group in thedefinitions for X, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ represents phenyl group,1-naphthyl group, 2-naphthyl group, anthracenyl group, etc.

The optionally substituted heteroaryl group in the definitions for X,R³, R⁴, R⁵, R⁶, R⁷and R⁸ represents a group derived from a monocyte or acondensed ring containing 1-4 of at least one selected from the groupconsisting of sulfur atom, oxygen atom and nitrogen atom. Its examplesare pyrrolyl group, thienyl group, furyl group, thiazolyl group,oxazolyl group, isothiazolyl group, isoxazolyl group, imidazolyl group,pyrazolyl group, thiadiazolyl group, oxadiazolyl group, triazolyl group,tetrazolyl group, pyridyl group, pridazinyl group, pyrimidinyl group,pyrazinyl group, indolyl group, isoindolyl group, benzothienyl group,benzofuranyl group, isobenzofuranyl group, benzimidazolyl group,indazolyl group, benzotriazolyl group, benzothiazolyl group,benzoxazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group,phthalazyl group, quinolxalyl group, naphthyrindinyl group, quinazolinylgroup and imidazopyridinyl group.

The protective group in the optionally protected carboxyl group in thedefinitions for R⁵ and R⁶ is, for example, a lower alkyl group such asmethyl group, ethyl group and tert-butyl group; a lower alkyl groupsubstituted with an optionally substituted phenyl group such asp-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,trityl and phenethyl groups; a halogenated lower alkyl group such as2,2,2-trichloroethyl and 2-iodoethyl; a lower alkanoyloxy lower alkylgroup such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl,1-pivaloyloxyethyl and 2-pivaloyloxyethyl; a higher alkanoyloxy loweralkyl group such as palmitoyloxyethyl, heptadecanoyloxymethyl and1-palmitoyloxyethyl; a lower alkoxycarbonyloxy lower alkyl group such asmethoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and1-(isopropoxycarbonyloxy) ethyl; a carboxy lower alkyl group such ascarboxymethyl and 2-carboxyethyl; a heteroaryl group such as3-phthalidyl; an optionally substituted benzoyloxy lower alkyl groupsuch as 4-glycyloxybenzoyloxymethyl; a (substituted dioxolene) loweralkyl group such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; acycloalkyl-substituted lower alkanoyloxy lower alkyl group such as1-cyclohexylacetyloxyethyl; a cycloalkyloxycarbonyloxy lower alkyl groupsuch as 1-cyclohexyloxycarbonyloxyethyl; etc. That may be also invarious acid amides. In short, any group may be a protective group forthe carboxyl group so far as it is decomposed in vivo by certain meansto give a carboxylic acid.

The term “a ring which is formed together with the nitrogen amino towhich they are bonded” in the definitions for R⁷, R⁸, R²¹ and R²²represents aziridine, azetidine, pyrrolidine, piperdine,perhydroazepine, perhydroazocine, piperazine, homopiperazine,morpholine, thiomorpholine, etc. Such a ring may be substituted with alower alkyl group, a halogen atom or acyl group, etc.

It goes without saying that, in the case of a compound having anasymmetric atom in the present invention, an optically active substancethereof is also covered by the present invention. The present inventionfurther covers a hydrate.

Examples of a pharmacologically acceptable salt in the present inventionare an inorganic salt such as hydrochloride, hydrobromide, sulfate andphosphate; an organic acid salt such as acetate, maleate, tartrate,methanesulfonate, benzenesulfonate and toluenesulfonate; and a salt withamino acid such as aspartic acid and glutamic acid.

A group of the compounds of the present invention is useful also fromthe viewpoint of low toxicity and high safety.

When the compound of the present invention is used for theabove-mentioned diseases, it may be administered either orally orparenterally. It may be administered in a form of a pharmaceuticalpreparation such as tablets, powder, granules, capsules, syrup, troche,inhalant, suppository, injection, ointment, ophthalmic ointment, eyedrops, nose drops, ear drops, poultice and lotion.

The dose significantly varies depending upon type of the disease, degreeof the symptom, age, sex and sensitivity of the patient, etc. but,usually, administration is carried out in a dose of about 0.03-1000 mg,preferably 0.1-500 mg, and more preferably 0.1-100 mg per day to anadult either once daily or dividing into several times a day. In thecase of an injection preparation, the dose is usually about 1 μg/kg to3000 μg/kg, preferably about 3 μg/kg to 1000 μg/kg.

In the manufacture of a pharmaceutical preparation of the compound ofthe present invention, that is carried out by a conventional means usinga common pharmaceutical carrier.

Thus, in the manufacture of a solid presentation for oral use, afteraddition of filler, binder, disintegrating agent, lubricant, coloringagent, corrective agents for taste and smell, antioxidant, etc. to themain ingredient, then the mixture is made into tablets, coated tablets,granules, powder, capsules, etc. by a conventional manners.

With regard to the above filler, its examples which may be used arelactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose,silicon dioxide, etc.

With regard to the binder, polyvinyl alcohol, polyvinyl ether, ethylcellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate,dextrin, pectin, etc. may be used for example while, with regard to thelubricant, magnesium stearate, talc, polyethylene glycol, silica,hydrogenated vegetable oil, etc. may be used for example.

With regard to the coloring agent, anything may be used so far as it ispermitted to add to pharmaceuticals. With regard to the correctiveagents for taste and smell, cocoa powder, menthol, aromatic acid,peppermint oil, borneol, cinnamon powder, etc. may be used. With regardto the antioxidant, anything may be used so far as it is permitted toadd to pharmaceuticals such as ascorbic acid and ^(α)-tocopherol. It isof course possible that tables and granules are appropriately coatedwith sugar, gelatin and others as required.

On the other hand, in the manufacture of injection, eye drops, etc., itis possible to manufacture by a conventional means by adding, ifnecessary, pH adjusting agent, buffer, suspending agent, auxiliarysolubilizer, stabilizer, isotonizating agent, antioxidant, preservative,etc. to the main ingredient. In that case, it is also possible toprepare a freeze-dried preparation, if necessary. The injection may beadministered intravenously, subcutaneously or intramuscularly.

Examples of the above-mentioned suspending agent are methyl cellulose,polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth,carboxymethyl cellulose sodium and polyoxyethylene sorbitan monolaurate.

Examples of the auxiliary solubilizer are polyoxyethylene hydrogenatedcastor oil, polysorbate 80, nicotinamide and polyoxyethylene sorbitanmonolaurate.

With regard to the stabilizer, sodium sulfite, sodium metasulfite,ether, etc. may be used for example while, with regard to thepreservative, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbicacid, phenol, cresol, chlorocresol, etc. may be used for example.

In the manufacture of the ointment, it can be manufactured by aconventional means by addition of stabilizer, antioxidant, preservative,etc. if necessary.

The novel purine compound of the present invention may be manufacturedby combining the commonly known methods. As hereunder, main commonmanufacturing methods for a group of the compounds of the presentinvention will be given.

Manufacturing Method A

In the above formulae, L¹ and L² represent halogen atom; R^(2′)represents —NR⁷R⁸ (wherein —NR⁷R⁸ has the meaning as defined above); R⁹represents a lower alkyl group; and R¹, R³ and R⁴ have the meaning asdefined above.

Step A1

This is a step where 4,6-dihalo-5-nitro-2-pyrimidinylacetamide 1 whichis a compound synthesized according to a known method is reacted with anamine compound in a solvent whereupon only one halogen is substitutedwith an amine compound to manufacture 4-aminopyrimidine compound 2.

There is no particular limitation for the solvent used therefor so faras it does not disturb the reaction and is able to dissolve the startingsubstance to some extent and its preferred examples are ether such astetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethylether; and a halogenated hydrocarbon such as methylene chloride,chloroform and dichloroehtane. The reaction temperature varies dependingupon the reactivity of the amine compound used and is preferably −20° C.to 50° C., and more preferably, about 0° C.

In this step, it is preferred to add an equimolar amount of acetic acidto suppress the production of a di-substituted substance.

Step A2

This is a step where a nitor group of the nitropyrimidine compound 2 isreduced by means of a catalytic reduction, a reduction with metal andmetal salt, or a metal hydride to manufacture a pyrimidinylaminecompound 3.

The catalytic reduction is carried out in a hydrogen atmosphere in thepresence of a catalyst such as Raney Ni, Pd—C or PrO₂ under ordinarypressure or high pressure at room temperature or with warming. There isno particular limitation for the solvent used so far as it does not actas a catalyst poison and is able to dissolve the starting material tosome extent and its suitable examples are methanol, ethanol,tetrahydrofuran, dioxane, acetic acid, dimethylformamide and a mixturethereof. Reduction with metal and metal salt is carried out using zincdust-hydrochloric acid, stannous chloride-hydrochloride acid,iron-hydrochloric acid, etc. in a solvent of an alcohol such asanhydrous methanol or ethanol or dioxane and tetrahydrofuan. Reductionusing a metal hydride is carried out in a solvent of methanol, ethanolor tetrahydrofuran using Pd-sodium borohydride, NiCl₂(PPh₃)₂— sodiumborohydride, stannous chloride-sodium borohydride, etc.

Step A3

This is a step where an amino group and an aldehyde which are adjacenton a pyrimidine ring is condensed with an imidazole ring to manufacturea purine compound 4.

The reaction is carried out in such a manner that an amino group iscondensed with an aldehyde compound to give Schiff base, and then it istreated with ferric chloride, etc. to result in a ring closure.

There is no particular limitation for the solvent used so far as it doesnot disturb the reaction and is able to dissolve the starting materialto some extent and its preferred examples are alcohol such as methanoland ethanol; ether such as tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; and dimethylformamide. The reaction iscarried out at 0 to 100° C., and preferably, at room temperature. It ispreferred to add acetic acid during the manufacture to Schiff base.

Step A4

This is a step where an acyl group which is a protecting group of theamino group at position 2 of the above purine compound A is eliminatedto manufacture a 2-aminopurine compound 5.

The reaction is carried out by means of a treatment with a mineral acidor an alkaline aqueous solution in a solvent such as methanol, ethanol,dioxane and tetrahydrofuran. Although the reaction proceeds even at roomtemperature, it is preferred to carry it out with heating.

This step may be completed in the above step A3 depending upon thereducing condition, and in that case, this step is omitted.

Step A5

This is a step where an amino group of the 2-aminopurine compound 5 issubjected to a Sandmeyer reaction to convert into a halogen atom tomanufacture a 2,6-dihalopurine compound 6.

The reaction is carried out in such a manner that the amino group isdiazotized with sodium nitrile or ester nitrous such as amyl nitrite andisoamyl nitrite to give a diazonium group and then the diazonium groupis converted to a halogen atom using cuprous halide. When a nitride suchas isoamyl nitrite is used in the diazotization, an acid is notparticularly necessary but the amino group can be converted to a halogenatom by addition of cuprous halide and methylene halide in a solventsuch as dioxane or tetrahydrofuran followed by heating. In the presentinvention, it is most preferred that cuprous iodide is used as a cuproushalide and diiodemethane is used as a methylene halide to convert into a2-iodopurine compound.

Step A6

This is a step where a halogen atom at position 2 of the2,6-dihalopurine compound f is selectively subjected to a couplingreaction with an ethynyl side chain to manufacture a2-ethynylene-6-halopurine compound 7.

The reaction is carried out at room temperature or with heating in thepresence of catalytic amounts of dichlorobistriphenylphosphine palladium(II) and cuprous iodide and a tertiary amine. Examples of the solventused are ether such as tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; dimethylformamide; and1-methylpyrrolidinone. Examples of the tertiary amine used aretriethylamine, diisopropylethylamine, DBU and dimethylaniline. Thereaction temperature is preferably 0 to 100° C., and more preferably,room temperature.

Step A7

This is a step where a halogen atom of the 2-ethynylene-6-halopurinecompound 7 is reacted with an amine compound to manufacture a6-amino-2-ethynylenepurine compound 8.

When the amine compound is gaseous or has a low boiling point, it ispreferred that the reaction is carried out in a sealed tube or in anautoclave.

There is no particular limitation for the solvent used so far as it doesnot disturb the reaction and is able to dissolve the starting materialto some extent and its preferred examples are alcohol such as methanoland ethanol; ether such as tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; halogenated hydrocarbon such asmethylene chloride, chloroform and dichloroethane; dimethylformamide;and 1-methylpyrrolidinone.

The reaction temperature is preferably 0 to 150° C., and morepreferably, 50 to 100° C.

Manufacturing Method B

In the above formula, L¹, R¹, R^(2′), R⁴ and R⁹ have the meanings asdefined above.

This manufacturing method B is another method for the manufacture of theb 2-acylamino-6-halo-5-nitro-4-pyrimidinylamine compound 3 in themanufacturing method A.

Step B1

This is a step where 2-acylamino-4-chloro-5-nitro-6-pyrimidine compound1 manufactured by a known method is reacted with an amine compound tomanufacture 2-acyl-amino-4-(substituted amino)-5-nitro-6-pyrimidonecompound 2.

There is no particular limitation for a solvent used so far as it doesnot disturb the reaction and is able to dissolve the starting materialto some extent and its preferred examples are ether such astetrahydrofuan, dioxane, dimethoxyethane and diethylene glycol dimethylether; and halogenated hydrocarbon such as methylene chloride,chloroform and dichloromethane. The reaction temperature variesdepending upon the reactivity of the amine compound used and it ispreferably −20° C. to 50° C., and more preferably, about 0° C.

Step B2

This is a step where an oxo group of the pyrimidone compound isconverted into a halogen atom to manufacture2-acylamino-6-halo-5-nitro-4-pyrimidinylamine compound 3.

The reaction is carried out in the absence of solvent or by suspendingin a solvent such as acetonitrile, dioxane or tetrahydrofuran and bytreating with a halogenating agent such as phosphorus oxychloride orphosphorus oxybromide with heating under reflux. The reaction isaccelerated when tetraethylammonium chloride or dimethylformamide isadded to the reaction system.

Manufacturing Method C

In the above formulae, L¹, L², R¹, R^(2′), R³ and R⁴ have the meaningsas defined above.

This manufacturing method C is that where L¹ at position 6 on a purinering of the 2,6-dihalopurine compound 6 in the manufacturing method A isfirstly aminated and then L² at position 2 is converted to an ethynylenegroup to manufacture the aimed compound.

Step C1

This is a step where a halogen atom at position 6 of the2,6-dihalopurine compound 1 is reacted with an amine compound tomanufacture a 6-amino-2-halopurine compound 2.

When the amine compound is gaseous or has a low boiling point, it isreferred that the reaction is carried out in an autoclave.

There is no particular limitation for the solvent used so far as it doesnot disturb the reaction and is able to dissolve the starting materialto some extent and its preferred examples are alcohol such as methanoland ethanol; ether such as tetrahydrofuran, dioxane, dimethoxyethane anddiethylene glycol dimethyl ether; halogenated hydrocarbon such asmethylene chloride, chloroform and dichloroethane, dimethylformamide;and 1-methylpyrrolidinone.

The reaction temperature is preferably 0 to 150° C., and morepreferably, 50 to 100° C.

Step C2

This is a step where the aimed compound is prepared by the sameoperation as in the above-mentioned step A6.

The reaction is carried out at room temperature or with heating in thepresence of catalytic amounts of dichlorobistriphenylphosphine palladium(II) and cuprous iodide and a tertiary amide. Examples of the solventused are ether such as tetrahydrofuran, dioane, dimethoxyethane anddiethylene glycol dimethyl ether; dimethylformamide; and1-methylpyrrolidinone. Examples of the tertiary amine used aretriethylamine, diisopropylethylamine, DBU and dimethylaniline. Thereaction temperature is preferably 0 to 100° C. and, more preferably,room temperature.

Manufacturing Method D

In the above formulae, Q is an alkylene group, an optionally substitutedarylene group; an optionally substituted heteroarylene group; anoptionally substituted alkylenearylene group; an optionally substitutedalkyleneheteroarylene group; an optionally substituted arylenealkylenegroup; or an optionally substituted heteroarylenealkylene group and R¹,R² and R³ having the meanings as defined above.

This manufacturing method D is a method where, in the case the compound1 manufactured by the manufacturing method A or C has a cyano group, thecyano group is converted whereupon an amide compound, an amidinecompound or an N-cyanoamidine compound is manufactured. Accordingly,when a cyano group is present on the substituents of R² and R³, theabove compounds can be manufactured in a similar manner.

Step D1

This is a step where an amide compound is manufactured from the cyanocompound 1 manufactured by the manufacturing method A or C.

The reaction is carried out by treating with an aqueous solution ofsodium hydroxide or potassium hydroxide in the presence of a peracid ina water-miscible solvent such as acetone, dioxane, tetrahydrofuran,methanol and ethanol. The reaction temperature is preferably from 0° C.to a refluxing temperature and, more preferably, room temperature.

Step D2

This is a step where an amidine compound is manufactured from the cyanocompound 1 manufactured by the manufacturing method A or C.

It is possible to manufacture by various methods. For example, amono-substituted substance may be manufactured by a method where a cyanocompound 1 is heated to 200° C. or higher with an equimolar aromaticamine benezenesulfonate or p-toluenesulfonate; an N,N-disubstitutedsubstance may be manufactured by a method where an amine compound isheated with a cyano compound 1 in the presence of a Lewis acid such asaluminum chloride; and an unsubstituted substance may be manufactured bya method where a cyano compound 1 is treated with an aluminum amidereagent (MeAlClNH₂) or by a method where it is converted into an imidatehydrochloride with hydrogen chloride-ethanol followed by treating withammonia. Alternatively, the mono- or di-substituted substance may bemanufactured by treating the imidate hydrochloride with a primary orsecondary amine.

Step D3

This is a step where an N²-cyanoamidine compound is manufactured fromthe cyano compound 1 manufactured by the manufacturing method A or C.

A cyano compound 1 is dissolved in dioxane or tetrahydrofuran, hydrogensulfide is passed thereinto to saturate, the mixture is allowed to standat room temperature to convert into thioamide, and then the thioamide istreated with iodomethane to give thiomidate. The thioimidate is treatedwith cyamide whereupon an N-cyanoamidine compound 4 is manufactured.When this operation is applied to a 2-iodo-6-purinylamine compoundmanufactured in the step C1 of the manufacturing method C and thefirstly prepared 2-iodo-N-cyanoamidine compound is coupled with analkyne reagent, a cyano compound 1 is manufactured in a similar manner.

Manufacturing Method E

(in the formula, R¹² represents a protective group for a carboxyl group;R¹³ and R¹⁴ are the same as or different from each other and eachrepresents hydrogen atom, an optionally substituted lower alkyl group,an optionally substituted aryl group or an optionally substitutedheteroaryl group; and R¹, R^(2′) and R³ have the meanings as definedabove.)

Step E1

This is a step where the protective group is eliminated by an acid or analkali or by means of heating to manufacture a carboxylic acid compound2.

Examples of the acid used are an aqueous solution of mineral acid suchas hydrochloric acid and sulfuric acid while examples of an alkali arean aqueous solution of sodium hydroxide, potassium hydroxide and lithiumhydroxide. With regard to a solvent, any solvent may be used so far asit does not participate in the reaction and that which is miscible withwater such as methanol, ethanol, tetrahydrofuran and dioxane ispreferred. Preferred reaction temperature is from room temperature torefluxing temperature.

When the protective group is tetrahydropyranyl group, it can beeliminated by heating at from 70 to 150° C.

Step E2

This is a step where the carboxylic acid compound 2 previously preparedis converted into a reactive derivative of the acid and made to reactwith a primary or secondary amine to manufacture an acid amide compound3.

Examples of the reactive derivative of the acid are an acid halide suchas acid chloride, a mixed acid anhydride such as ethoxycarbonyl chlorideobtained by the reaction with chloroformate; and an activated ester suchas p-nitrophenyl ester. Examples of the solvent are tetrahydrofuran,dioxane, dichloromethane, chloroform and dichloroethane. The reactiontemperature is preferably from −10 to 50° C., and more preferably, from0° C. to room temperature.

Step E3

This is a step where the ester compound 1 is reacted with an aminecompound to directly manufacture an acid amide compound 3 without by wayof a carboxylic acid compound 2.

With regard to a protective group R¹², a lower alkyl group such as amethyl group or an ethyl group is preferred. The reaction is carried outby heating in a sealed tube or in an autoclave. The reaction temperatureis preferably from 50 to 100° C.

The above eliminating reaction and amidation reaction can be used forthe case where R¹ or R³ has a protected carboxyl group as well tomanufacture a product.

Manufacturing Method F

(in the formulae, n represents an integer of from 2 to 6 and R^(2′), R³,R¹², R¹³ and R¹⁴ have the meanings as defined above.)

Step F1

This is a step where a purine compound 1 having a hydroxyl-substitutedalkyl group is oxidized to manufacture a carboxylic acid compound 2.

With regard to an oxidizing agent, ruthenium tetraoxide, permanganicacid, chromic acid, etc. may be used. With regard to a solvent, carbontetrachloride, chloroform, methylene chloride, acetonitrile, pyridine,water or a mixed solvent thereof may be used. The reaction is carriedout preferably at 0 to 50° C., and more preferably, at room temperature.

A carboxylic group of the carboxylic acid compound 2 manufactured assuch is then protected and, after that, conversion into a2-ethynylenepurine compound is carried out by the same operation as inthe step A6 of the manufacturing method A.

When there is a hydroxyl-substituted alkyl group is present in R³, thesame method is applied whereupon a 2-ethynylenepurine compound having acarboxylic group in R³ is manufactured by the same method.

Manufacturing Method G

(in the formulae, R^(2′) is an amino group or a halogen atom; and R1, R³and R⁴ have the meaning as defined above.)

Step G1

This is a step where the amino group or the halogen atom at position 6of the purine skeleton is hydrolyzed to manufacture a 6-hydroxypurinecompound 2.

The hydrolysis is carried out in the presence of an acid or an alkaliand it is preferred to carry out in the presence of an alkali. Examplesof the alkali used are sodium hydroxide, potassium hydroxide, etc. Thereaction is carried out at from 0 to 100° C.

Step G2

This is a step where the amino group at position 6 is diazotized andheated to eliminate the nitrogen whereupon a 6-unsubstituted purinecompound is manufactured.

The reaction is carried out in such a manner that the amino group isdiazotized with sodium nitrite or nitrous ester such as amyl nitrite,isoamyl nitrite, etc. in dioxane, tetrahydrofuran or an aqueous solventthereof and then the diazonium group is eliminated by heating underrefluxing.

Incidentally, a method for the manufacture of the compound representedby the formula (VII) is described in JP-A 6-16559 and JP-A-211856, J.Med. Chem., 36, 1333-1342, 1993, etc.; a method for the manufacture ofthe compound represented by the formula (VIII) is described in JP-A5-97855 and WO 94/14812; a method for the manufacture of the compoundrepresented by the formula (IX) is described in WO 95/01356 and Eur. J.Med. Chem., 28, 569-576, 1993.; and a method for the manufacture of thecompound represented by the formula (X) is described in WO 98/42711.

Now, in order to explain the excellent effect of the purine compounds ofthe present invention, pharmacological experiments will be shown ashereunder.

Effects of Novel Purine Compounds

1) Suppressing Action to NECA-Stimulated Saccharogenesis GlucoseProduction in Hepatic Cells of Primary Culture of Rats

Hepatic cells were separated by a collagenase perfusion method fromliver of male rats of Wistar strain and subjected to a primary culturein a William's Medium E containing 5% of calf serum, 10⁻⁶ M ofdexamethasone and 30 ng/ml of pertussal pertussis toxin. After one day,the hepatic cells were washed with a Krebs-Ringer Bicarbonate buffer (pH7.4 (KRB)) containing 10 mM of HEPES and 0.1% of bovine serum albuminand incubated with KRB at 37° C. After 30 minutes, 0.1 μM of NECA(N-ethylcarboxamide adenosine) and a test compound were added thereto atthe same time, the mixture was incubated for additional one hour and theamount of glucose released into an incubation medium was measured.

The result is shown in Table 1.

TABLE 1 Suppressing Action to NECA-Stimulated SaccharogenesisGlucoseProduction in Hepatic Cells of Primary Culture of Rats Example 8 0.49(sulfate) Example 19 0.47 Example 31 0.13 Example 64 0.73 (sulfate)Example 89 0.43 Example 133 0.20 Example 169 0.48 Example 170 0.50Example 171 1.01 Example 208 0.27 Example 210 0.52 Example 215 0.22Example 235 1.27

2) Action to Hyperglycemia of Spontaneous Diabetic Mice (KK-A^(y)/TaJcl) (Single Administration)

-   -   Animals: Five male KK-A^(y)/Ta Jcl mice for each group        (purchased from Nippon Clair)    -   Preparation and Administration of Test Compound: A test compound        in a dose as shown in Table 1 was suspended in a 0.5% aqueous        solution of methyl cellulose and was orally administered in a        dose volume of 10 ml/kg.    -   Collection of Blood Samples and Determination of Blood Sugar:        Glucose: Blood was collected from tail vein immediately before        adminstration of the test compound and also five hours after the        administration and blood sugar glucose was determined.    -   Method: Tail vein of a mouse was injured by a razor without an        anesthetization to bleed slightly. The blood (15 μl) was        collected and immediately mixed with 135 μl of a 0.6 M        perchloric acid. Glucose in the supernatant obtained by a        centrifugal separation (at 1500 g for 10 minutes at 4° C. using        a cooling centrifuge GS-6KR of Beckmann) was determined by a        Glucose CII Test Wako (Wako Pure Chemicals).

The result for each experiment is shown in Table 2-1 to 2-3.

The result is shown in terms of “(% ratio of the blood sugar glucoseafter 5 hours from the administration to the blood sugar glucose beforethe administration)±(standard error)”. The data were subjected to aone-way layout analysis of variance and then subjected to a multiplecomparison of a Dunnett type. The case where p<0.05 was judged to bethat a significant difference was available.

TABLE 2-1 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{{immediately}\quad{before}}\quad} \\{{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 72.4 ± 4.4 Example 8 1047.8 ± 4.8 ** (sulfate) Example 19 10 51.8 ± 2.9 ** (**; p < 0.01 vs.Solvent)

TABLE 2-2 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 67.6 ± 2.4 Example 6410 42.3 ± 4.8 ** Example 89 30 38.3 ± 4.4 ** (**; p < 0.01 vs. Solvent)

TABLE 2-3 Action of Spontaneous Diabetic Mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 70.7 ± 4.6 Example 21010 51.5 ± 4.6 * (*; p < 0.05 vs. Solvent)

As such, the compounds of the present invention showed a clear effect tothe pathological models. In addition, the compounds of the presentinvention showed an improving action in the investigation for impairedglucose tolerance in a glucose tolerance test and were confirmed to actnot only in liver but also in periphery.

Now, representative compounds of the novel purine compounds according tothe present invention will be illustrated and it goes without sayingthat the object is to facilitate the understanding of the presentinvention and that the present invention is not limited thereby.

EXAMPLE 13-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzonitrile

1)N¹-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide

To a solution of 2.54 g of 3-cyanoaniline in 25 ml of tetrahydrofuranwere gradually added 1.23 ml of acetic acid at 0° C. To this solutionwere added 2 g of4-chloro-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinylacetamide at 0° C. andthe mixture was stirred for 3.5 hours. The reaction solution wasfiltered and the solid collected thereby was washed with 10 ml each ofwater, methanol, tetrahydrofuran and ether successively. The resultingproduct was dried at room temperature to give 2.58 g ofN¹-[4-(3-cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide.The yield was 96%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 2.18 (s, 3H), 7.56-7.60 (m,1H), 7.67-7.70 (m, 1H), 7.83-7.87 (m, 1H), 8.07 (s, 1H), 11.05 (s, 1H),11.69 (br s, 2H).

2) N¹-[4-Chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide

N¹-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]acetamide(2.5 g) was suspended in 50 ml of acetonitrile, then 2.64 g oftetraethylammonium chloride, 1 ml of N,N-dimethylaniline and 4.5 ml ofphosphorus oxy-chloride were added and the mixture was heated underreflux for 5 hours. The reaction solution was returned to roomtemperature and added to ice-water and the mixture was stirred for 30minutes. The resulting crystals were collected by filtration washed withwater and dried to give 2.5 g ofN¹-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide. Theyield was 93%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆) 2.18 (s, 3H), 7.56-7.60 (m, 1H),7.67-7.70 (m, 1H), 7.83-7.87 (m, 1H), 8.07 (s, 1H), 11.05 (s, 1H), 11.69(br s, 2H).

2) 3-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino]benzontrile

N¹-[4-Chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide (2.37 g)was dissolved in 237 ml of ethanol, 8.04 g of stannous chloride wasadded and then 135 mg of sodium borohydride was added thereto withheating at 60° C. After stirring at 60° C. for 3 hours, the mixture wasreturned to room temperature and concentrated to dryness. The resultingresidue was diluted with water and the resulting precipitates werecollected by filtration and washed with water to give 3.2 g of crudecrystals of 3-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile.This was used for the next step without purification.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 4.24 (s, 2H), 6.08 (s, 2H),7.38-7.42 (m, 1H), 7.44-7.49 (m, 1H), 7.97-8.02 (m, 1H), 8.31-8.34 (m,1H), 8.62 (s, 1H).

4) 3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile

Crude crystals (3.2 g) of3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile were dissolvedin 64 ml of methanol, then 3.2 ml of acetic acid and 1.7 ml of3-fluorobenzaldehyde were added thereto and the mixture was stirred atroom temperature for 2 hours. The reaction solution was concentrated andwas subjected to an azeotropy with toluene for two times. The resultingresidue after concentration was dissolved in ethanol, a solution of 1.72g of ferric chloride in 10 ml of ethanol was added and the mixture washeated under reflux for 1 hour. The reaction solution was returned toroom temperature, concentrated to dryness and added to ice-water and theresulting crystals were collected by filtration to give 2.6 g of thetitle compound, i.e.,3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile.

NMR (400 MHz, δ, δ, CDCl₃); 5.09 (s, 2H), 7.06-7.10 (m, 1H), 7.11-7.15(m, 1H), 7.18-7.28 (m, 2H), 7.40-7.44 (m, 1H), 7.53-7.57 (m, 1H),7.62-7.64 (m, 1H), 7.70-7.73 (m, 1H).

5) 3-[6-Chloro-8-(3-fluorophenyl-2-iodo-9H-9-purinyl]benzonitrile

3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-benzonitrile (2.6g) was dissolved in 105 ml of tetrahydrofuran, then 2.9 ml of isoamylnitrite, 5.8 ml of diiodomethane and 1.37 g of cuprous iodide were addedthereto and the mixture was heated under reflux for 1 hour. After theresulting mixture was cooled to room temperature, it was filtered toremove unnecessary substances and washed with 100 ml of ethyl acetate.The filtrate was concentrated to dryness and purified by a silica gelcolumn (50 g of silica gel). It was eluted with ethyl acetate and hexane(1:1). The fractions containing the aimed product were collected,concentrated and suspended in 100 ml of a mixed solvent of ethyl acetateand hexane (1:4), and the resulting precipitates were collected byfiltration to give 1.7 g of3-[(6-chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile. Theyield was 50%.

NMR (400 MHz, δ, δ, CDCl₃); 7.19-7.27 (m, 2H), 7.31-7.40 (m, 2H),7.57-7.60 (m, 1H), 7.64-7.66 (m, 1H), 7.53-7.57 (m, 1H), 7.68-7.72 (m,1H), 7.84-7.87 (m, 1H),

6)3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzonitrile

1-3-[6-Chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile (2.1g) was dissolved in 54 ml of dioxane, then 660 mg of1-ethynylcyclohexanol, 310 mg of bis-triphenylphosphine palladiumdichloride, 169 mg of cuprous iodide and 0.39 ml of trethylamine wereadded thereto and the mixture was stirred at room temperature in anitrogen atmosphere for hours. The reaction solution was diluted with100 ml of dichloromethane and washed with 100 ml of a saturatedethylenediaminetetraacetic acid. The organic layer was washed with 20 mlof brine and dried over anhydrous sodium sulfate. After the resultingsolution was concentrated to dryness, the resulting residue wassuspended in 100 ml of dichloromethane and the resulting crystals werecollected by filtration to give 1.8 g of3-{6-chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H9-purinyl}benzonitrile. The yield was 86%. NMR (400 MHz, δ, δ, CDCl₃);1.27-1.40 (m, 1H), 1.57-1.78 (m, 7H), 2.01-2.08 (m, 2H), 2.13 (s, 1H),7.18-7.24 (m, 1H), 7.25-7.28 (m, 1H), 7.32-7.40 (m, 2H), 7.55-7.58 (m,1H), 7.66-7.72 (m, 2H), 7.83-7.86 (m, 1H).

7)3-[6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxyhexyl)-1-ethynyl]-9H-9-purinyl]benzonitrile

3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]benzonitrile(2.0 g) was suspended in 200 ml of a 20% ammonia/ethanol and reacted at100° C. in an autoclave for 8 hours. The resulting mixture was cooled toroom temperature, concentrated to dryness and purified by a silica gelcolumn (40 g of silica gel). It was eluted with dichloromethanecontaining 5% of methanol. The fractions containing the aimed productwere collected, concentrate to dryness, suspended in 100 ml of a mixedsolvent of ethyl acetate and hexane (1:1) and the resulting product wascollected by filtration and washed with hexane to give 1.4 g of thetitle compound. The yield was 73%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.26-1.41 (m, 1H), 1.46-1.75(m, 7H); 1.99-2.07 (m, 2H), 2.32 (s, 1H), 5.81 (br s, 2H), 7.12-7.18 (m,2H), 7.21-7.25 (m, 1H), 7.30-7.36 (m, 1H), 7.54-7.57 (m, 1H), 7.60-7.64(m, 1H), 7.68-7.70 (m, 1H), 7.75-7.79 (m, 1H).

Compounds of Example 2 to Example 11 were synthesized by the same manneras in Example 1 using the corresponding material and they were allobtained as hydrochlorides by a conventional method.

EXAMPLE 21-{2-[6-Amino-8-(3-fluorophenyl)-9-phenyl-9H-2-purinyl]-1-ethynyl}1-cyclohexenolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.16-1.28 (m, 1H) 1.37-1.63 (m,7H), 1.72-1.80 (m, 2H), 7.22-7.26 (m, 3H), 7.36-7.42 (m, 3H), 7.50-7.57(m, 3H), 7.68 (br s, 1H). FAB MASS; 428 (M⁺+1).

EXAMPLE 31-{2-[6-Amino-9-[4-(dimetylamino)phenyl]-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.28 (m, 1H), 1.38-1.62(m, 7H), 1.74-1.82 (m, 2H), 2.98 (s, 6H), 6.87 (d, J=8.7 Hz, 2H), 7.14(d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H),7.23-7.33 (m, 3H), 7.90-8.45 (m, 1H), m.p.; 255-260° C.; FAB MASS; 471(M⁺+1).

EXAMPLE 41-[6-Amino-8-(3-fluorophenyl)-9-(4-morpholinophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.40-1.64(m, 7H), 1.74-1.82 (m, 2H), 3.20 (br, 4H), 3.76 (br, 4H), 7.06 (d, J=9.2Hz, 2H), 7.23 (d, J=9.2 Hz, 2H), 7.06 (d, J=9.2 Hz, 2H), 7.23 (d, J=9.2Hz, 2H), 7.24-7.34 (m, 3H), 7.39-7.45 (m, 1H). FAB MASS; 513 (M⁺+1).

EXAMPLE 51-{2-[6-Amino-8-(3-fluorophenyl)-9-(4-methoxyphenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.17-1.28 (m, 1H), 1.40-1.64(m, 7H) 1.75-1.84 (m, 2H), 3.80 (s, 3H), 7.08 (d, J=8.3 Hz, 2H),7.26-7.29 (m, 3H), 7.34 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H),7.26-7.29 (m, 3H), 7.34 (d, J=8.3 Hz, 2H), 7.39-7.45 (m, 1H), FAB MASS;458 (M⁺+1).

EXAMPLE 62-Amino-5-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzonitrileDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.16-1.30 (m, 1H), 1.35-1.64(m, 7H), 1.72-1.85 (m, 2H), 6.85 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz,1H), 7.25-7.36 (m, 4H), 7.42-7.49 (m, 1H), 7.55 (d, J=2.4 Hz, 1H). 7.55(d, J=2.4 Hz, 1H). FAB MASS 458 (M⁺+1).

EXAMPLE 74-{(6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzonitrileHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.17-1.28 (m, 1H), 1.36-1.64(m, 7H), 1.73-1.81 (m, 2H), 7.18-7.20 (m, 1H), 7.27-7.32 (m, 2H),7.39-7.45 (m, 1H), 7.64 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H). 7.64(d, J=8.4 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H). FAB MASS; 453 (M⁺+1).

EXAMPLE 81-{2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.33 (t, J=7.2 Hz, 3H), 1.33 (t, J=7.2 Hz,3H), 1.78-1.90 (m, 2H), 2.20-2.36 (m, 2H), 2.40-2.50 (m, 2H), 4.39 (q,J=7.2 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 6.19 (s, 1H), 7.51-7.57 (m, 1H),7.70-7.76 (m, 3H). FAB MASS; 352 (M⁺+1); m.p.; 160-163° C.

EXAMPLE 91-[(6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (t, J=7.2 Hz, 6H), 1.27 (t, J=7.2 Hz,3H), δ, DMSO-d ₆); 1.01 (t, J=7.2 Hz, 6H), 1.27 (t, J=7.2 Hz, 3H),1.60-1.75 (m, 4H), 4.30 (q, J=7.2 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H),7.44-7.50 (m, 1H), 7.63-7.70 (m, 3H). FAB MASS; 368 (M⁺+1); m.p.;150-153° C.

EXAMPLE 104-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-1-buthyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.32 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.32(t, J=7.2 Hz, 3H), 1.52 (s, 6H), 4.39 (q, J=7.2 Hz, 2H), 4.39 (q, J=7.2Hz, 2H), 5.76 (s, 1H), 7.51-7.57 (m, 1H), 7.60-7.75 (m, 3H). FAB MASS;340 (M⁺+1); m.p.; 193-196° C.

EXAMPLE 11 Ethyl3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzoate

NMR (400 MHz, δ, δ, CDCl₃); 1.24-1.42 (m, 1H), 1.37 (t, J=7.1 Hz, 3H),1.37 (t, J=7.1 Hz, 3H), 1.47-1.55 (m, 1H), 1.46-1.78 (m, 6H), 1.97-2.08(m, 2H), 2.48 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H),5.83 (br s, 2H), 7.06-7.12 (m, 1H), 7.17-7.21 (m, 1H), 7.22-7.31 (m,2H), 7.48-7.53 (m, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H),7.98-8.02 (m, 1H), 8.14-8.18 (m, 1H).

EXAMPLE 123-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycylohexyl)-1-ethynyl]-9H-9-purinyl}benzamideHydrochloride

3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzonitrile(1.4 g) obtained in Example 1 was dissolved in 70 ml of methanol, then1.55 ml of a 30% aqueous hydrogen peroxide and 1.55 ml of a 1N aqueoussolution of sodium hydroxide were added thereto and the mixture wasstirred for 4 hours. The resulting crystals were collected byfiltration, washed with water and dried to give 1.14 g of a freecompound of the title compound. The free compound was suspended in 30 mlof ethanol, 5 ml of a 6N aqueous solution of hydrochloric acid wereadded and the mixture was concentrated to dryness. The resulting residuewas suspended in 50 ml of diethyl ether, filtered, washed and then driedto give 1.2 g of the title compound. The yield was 76%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.15-1.28 (m, 1H), 1.25-1.63(m, 7H), 1.72-1.80 (M, 2H), 7.22-7.30 (m, 3H), 7.37-7.43 (m, 1H),7.54-7.58 (m, 1H), 7.60-7.64 (m, 1H), 7.77 (br s, 1H), 7.89-7.91 (m,1H), 8.01-8.04 (m, 1H), 8.08 (s, 1H), FAB MASS; 471 (M⁺+1).

Compounds of Examples 13 and 14 were obtained by the same manner as inExample 12.

EXAMPLE 134-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]benzamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆) 1.16-1.28 (m, 1H), 1.35-1.64 (m,7H), 1.72-1.81 (m, 2H), 7.22-7.29 (m, 3H), 7.39-7.44 (m, 1H), 7.50 (d,J=8.2 Hz, 2H), 7.55 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz,2H), 7.55 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 8.13 (s, 1H. FAB MASS; 471(M⁺+1).

EXAMPLE 142-Amino-5-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl--ethynyl}-9H-9-purinyl]benzamideDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆) 1.14-1.27 (m, 1H), 1.27-1.63 (m,7H), 1.65-1.82 (m, 2H), 6.79-6.84 (m, 1H), 7.17-7.18 (m, 1H), 7.19 (brs, 1H), 7.24-7.30 (m, 1H), 7.33-7.38 (m, 2H), 7.42-7.48 (m, 1H),7.60-7.63 (m, 1H), 7.72 (br s, 1H). FAB MASS; 486 (M⁺+1).

EXAMPLE 151-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}9H-purinyl]benzoicAcid Hydrochloride

An ethyl ester of Example 11 was dissolved in ethanol, a 1N aqueoussolution of sodium hydroxide was added and the mixture was stirred atroom temperature. After the reaction solution was concentrated, theresulting residue was dissolved in small amount of water, the solutionwas adjusted to pH 2 with 1N hydrochloric acid and the resultingcrystals were collected by filtration and washed with water and ether togive the title compound.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.18-1.28 (m, 1H), 1.36-1.62(m, 7H), 1.72-1.81 (m, 2H), 7.20-7.28 (m, 2H), 7.37-7.42 (m, 1H),7.63-7.69 (m, 3H), 7.93-7.95 (m, 1H), 8.04-8.07 (m, 1H), FAB MASS; 472(M⁺+1).

EXAMPLE 164-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]benzoicAcid Hydrochloride

The title compound was obtained by the same manner as in Example 15.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.16-1.28 (m, 1H), 1.37-1.64(m, 7H), 1.72-1.83 (m, 2H), 7.20-7.22 (m, 1H), 7.27-7.32 (m, 2H),7.39-7.44 (m, 1H), 7.54 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H). 7.54(d, J=8.4 Hz, 2H), 8.07 (i d, J=8.4 Hz, 2H). FAB MASS; 472 (M⁺+1).

EXAMPLE 173-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]benzenecarboxamidineDihydrochloride

A cyano compound of Example 1 was treated with MeAlClNH₂ to give thetitle compound.

NMR (400 MHz, δ, δ,CD₃OD); 1.34-1.47 (m, 1H), 1.60-1.86 (m, 7H),2.00-2.11 (m, 2H), 7.26-7.34 (m, 1H), 7.36-7.52 (m, 3H), 7.62-7.67 (m,1H), 7.78-7.84 (m, 1H), 8.02-8.08 (m, 1H), 8.13-8.17 (m, 1H), FAB MASS;470 (M⁺+1).

EXAMPLE 18N²-Cyano-{3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}benzene}carboxamidineDihydrochloride

3-[6-Chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl] benzonitrileobtained in the fourth step of Example 1 was treated with ammonia togive 3-{6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl}benzonitrile.This was treated with hydrogen sulfide to convert the cyano group tothioamide and then alkylated with iodomethane to give a methylthioimidate. This was reacted with cyanamide to giveN²-cyano-{3-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]-benzene}carboxamidine.After that, like in the sixth step of Example 1, the resulting compoundwas dissolved in dioxane, then 1-ethynylcyclohexanol,bis-triphenylphosphine palladium dichloride, cuprous iodide andtriethylamine were added thereto and the mixture was reacted at roomtemperature in a nitrogen atmosphere to give the title compound.

NMR (400 MHz, δ, δ, CD₃OD); 1.37-1.49 (m, 1H), 1.59-1.88 (m, 7H),2.02-2.13 (m, 2H), 7.29-7.35 (m, 1H), 7.36-7.40 (m, 1H), 7.44-7.51 (m,2H), 7.79 (t, J=8.1 Hz, 1H), 7.79 (t, J=8.1 Hz, 1H), 8.09-8.14 (m, 1H),8.17-8.24 (m, 1H). FAB MASS; 495 (M⁺+1).

EXAMPLE 191-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolSulfate 1) N¹-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide

A mixed solution (reagent A) of 2 liters of a 40% aqueous solution ofmethylamine and 1.5 liters of acetic acid previously prepared at nothigher than 10° C. was weighed and taken out in an amount of 1.8 litersand added dropwise into a solution of 1.5 kg ofN¹-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide in 15 liters oftetrahydrofuran with stirring under ice-cooling over 1 hour. Theaddition was carried out keeping the bulk temperature at 4° C. or lower.After the mixture was stirred for 30 minutes under ice-cooling, 450 mlof the reagent. A was further added. After further 30 minutes, 450 ml ofthe reagent A was added again followed by stirring for 40 minutes. Ice(4.5 kg) was added to the reaction mixture followed by adding 10 litersof cold water. The resulting crystals were collected by filtration andwashed with 1 liter of water twice and with 1 liter of ether twice. Thenit was dried at 50° C. for 6 hours to give 1253 g ofN¹-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide. The yieldwas 85%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 2.27 (s, 3H), 2.97 (d, J=4.4Hz, 3H), 8.55 (d, J=4.4 Hz, 1H), 2.97 (d, J=4.4 Hz, 3H), 8.55 (d, J=4.4Hz, 1H), 10.80 (s, 1H).

2) 6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine

N¹-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide (2050 g) wassuspended in 20 liters of methanol, 2 liters of acetic acid were addedand 2 kg of Raney nickel (used after washing with water and methanol)were added and the mixture was stirred in hydrogen for 12 hours. Thereaction solution was diluted with 20 liters of tetrahydrofuran andfiltered through Celite. The residue was washed with methanol for threetimes (3×1 liter), then washed with a mixed solvent of methanol andtetrahydrofuran (1:1) and combined with the filtrate and the mixture wasconcentrated to dryness. The resulting residue was subjected to anazeotropy with toluene, the residue was dissolved in 20 liters ofmethanol, then 276 ml of acetic acid and 1 liter of 3-fluorobenzaldehydewere added and the mixture was stirred at room temperature for 12 hours.The reaction solution was concentrated and subjected to an azeotropywith toluene. Concentrated residue was suspended in 17 liters ofethanol, 3 liters of ethanol solution of 1.5 kg of anhydrous ferricchloride were added and the mixture was heated under reflux for 1 hour.The reaction solution was returned to room temperature and concentratedto dryness and the residue was diluted with 12 liters of ethyl acetatefollowed by washing with 12 liters of water and 4.5 liters of brine. Theorganic layer was concentrated to dryness, the residue was dissolved in10 liters of tetrahydrofuran, 1.96 liters of a 1N hydrochloric acid wereadded thereto and the mixture was heated under reflux for 30 minutes.The reaction solution was cooled to room temperature, 10 kg of ice wereadded and the mixture was further diluted with 10 liters of water. Theresulting crystals were collected by filtration and washed with watertwice (2×1 liter) and with ether twice (2×1 liter) to give 1.0 kg of6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl-amine. The overallyield was 47%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.73 (s, 3H), 7.01 (s, 2H),7.40-7.46 (m, 1H), 7.60-7.66 (m, 1H), 7.68-7.74 (m, 2H).

3) 6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine

6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine (960 g) wasdissolved in 9.6 liters of tetrahydrofuran and then 774.3 g of cuprousiodide and 1.49 liters of diodomethane were added thereto. Isoamylnitrite (1.49 liters) was added dropwise during 1 hour into the mixturewith heating under reflux. The reaction solution was heated under refluxfor 15 minutes, cooled, diluted with 4 liters of ethyl acetate and thenfiltered through Celite followed by washing with ethyl acetate threetimes (3×2 liters). The filtrate and the washings were combined andwashed with 8 liters of water and 8 liters of brine. The organic layerwas dried over 2 kg of anhydrous sodium sulfate and concentrated toabout 3 liters. The concentrated solution was diluted with 10 liters ofhexane and the resulting crystals were filtered and washed with 1 literof hexane. The crystals were then dried at 50° C. for 4 hours to give1076 g of 6-chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine. Theyield was 75%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.89 (s, 3H), 7.49-7.56 (m,1H), 7.66-7.72 (m, 1H), 7.76-7.82 (m, 2H).

4)1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (1076 g) wasdissolved in 10 liters of tetrahydrofuran and 97.2 g ofbistriphenylphosphine palladium dichloride, 26.4 g of cuprous iodide and248 g of 1-ethynylcyclopentanol were added thereto. Into this mixturewere added dropwise 331 ml of triethylamine within 15 minutes keepingthe bulk temperature at not higher than 26° C. in a nitrogen atmosphere.After reacting at room temperature for 4 hours, the reaction solutionwas diluted with 10 liters of ethyl acetate and washed with 4 liters ofa saturated ammonium chloride solution and 1 liter of brine. The organiclayer was dried over 2 kg of anhydrous sodium sulfate and filteredfollowed by concentrating to an extent of 3 liters. The resultingresidue was diluted with 4 liters of hexane-ethyl acetate (1:1),filtered and washed with 1 liter of hexane to give 732 g of1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol.The yield was 88%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.67-1.85 (m, 4H), 1.87-2.03(m, 4H), 3.92 (s, 3H), 5.61 (s, 1H), 7.50-7.56 (m, 1H), 7.66-7.73 (m,1H), 7.78-7.84 (m, 2H).

5)1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyclopentanol(732 g) was dissolved in 16 liters of dimethoxyethane, 8 liters of aconcentrated aqueous ammonia were added and the mixture was stirred at70° C. for 5 hours using a sealed tube reactor. After the reactionsolution was cooled in room temperature, it was diluted with 20 litersof ethyl acetate and washed with water twice (8 liters and 4 liters).The organic layer was concentrated to about 15 liters and the resultingresidue was diluted with 15 liters of hexane, filtered and washed withhexane twice. Then it was dried at 50° C. for 2.5 hours to give 620 g ofthe product. The yield was 89%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.78 (m, 4H), 1.79-1.95(m, 4H), 3.78 (s, 3H), 5.41 (br s, 1H), 7.36-7.50 (m, 3H), 7.58-7.72 (m,3H).

6)1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl]-1-cyclopentanolSulfate

1-{2-(6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol(1.59 g) was suspended in 10 mL of methanol and 1 mL of a methanolsolution of 440 mg of concentrated sulfuric acid was added dropwisethereinto at room temperature. The resulting solution was evaporateduntil the amount of the solution became about one half followed byadding 4 mL of ether thereto. The resulting crystals were collected byfiltration, washed with ether and dried to give 1.79 g of the sulfate.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.80 (m, 4H), 1.82-1.98(m, 4H), 3.80 (s, 3H), 7.40-7.46 (m, 1H), 7.60-7.72 (m, 3H), 8.01-8.03(m, 1H).

A hydrochloride was prepared by a conventional method.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.66-1.82 (m, 4H), 1.87-2.00(m, 4H), 3.86 (s, 3H), 7.43-7.50 (m, 1H), 7.63-7.70 (m, 1H), 7.71-7.77(m, 2H). FAB MS; 352 (M⁺+1); m.p.; 230-232° C.

The compounds of Examples 20-68, 70-201, 203 and 205 were prepared bythe same manner as in Example 19 using the corresponding materials.

EXAMPLE 20 4-[-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-3-butyn-1-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 2.58 (t, J=6.7 Hz, 2H), 3.59 (t, J=6.7 Hz,2H), 3.88 (s, 3H), 6.77 (dd, J=1.7 Hz, 3.6 Hz, 1H), 7.25 (d, J=3.6 Hz,1H), 8.00 (d, J=1.7 Hz, 1H). δ, DMSO-d ₆); 2.58 (t, J=6.7 Hz, 2H), 3.59(t, =6.7 Hz, 2H), 3.88 (s, 3H), 6.77 (dd, J=1.7 Hz, 3.6 Hz, 1H), 7.25(d, J=3.6 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H). m.p.; 161-164° C.

EXAMPLE 21 8-(2-Furyl)-2-(1-hexynyl)-9-methyl-9H-6-purineamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 2.62 (t, J=6.7 2H), 3.79 (t, J=6.7 2H),DMSO-d ₆); 2.62 (t, J=6.7 2H), 3.79 (t, J=6.7 2H), 3.98 (s, 3H), 6.60(m, 1H), 7.10 (m, 1H), 7.62 (m, 2H). m.p.; 178-181° C.

EXAMPLE 22N-[8-(2-Furyl)-9-methyl-2-(2-phenyl-1-thienyl)-9H-6-pyrinyl]-N-phenethylamineHydrochloride

NMR (400 MHz, δ, δ, CDCl₃); 3.10 (br, 2H), 4.12 (s, 3H), 3.98 (s, 3H),4.19 (br, 1H), 4.38 (m, 2H), 6.68 (m, 1H), 6.72 (br, 1H), 7.20-7.53 (m,9H). m.p.; 148-151° C.

EXAMPLE 23 4-[6-Amino-8-(2-furyl)-9-methyl-9H-2-piurinyl]-3-butyn-2-ol

NMR (400 MHz, δ, d₆-DMSO); 1.36 (d, J=7.5 Hz, 3H), δ, DMSO-d ₆); 1.36(d, J=7.5 Hz, 3H), 3.84 (s, 3H), 4.45-4.60 (m, 1H), 5.56 (d, J=7.5 Hz,1H), 5.56 (d, J=7.5 Hz, 1H), 6.74 (m, 1H), (7.20 (d, J=3.5 Hz, 1H), 7.20(d, J=3.5 Hz, 1H), 7.46 (s, 2H), 7.98 (s, 1H).

EXAMPLE 241-[6-Amino-8-(2-furyl)-9-ethyl-9H-2-purinyl]-4-methyl-1-pentyn-3-ol

NMR (400 MHz, δ, d₆-DMSO); 0.96 (t, J=7.5 Hz, 6H), δ, DMSO-d ₆); 0.96(t, J=7.5 Hz, 6H), 1.76-1.86 (m, 1H), 3.84 (s, 3H), 4.20 (m, 1H), 5.52(d, J=7.5 Hz, 1H), 6.76 (dd, J=1.5 Hz, 3.7 Hz, 1H), 7.20 (d, J=3.7 Hz,1H), 5.52 (d, J=7.5 Hz, 1H), 6.76 (dd, J=1.5 Hz, 3.7 Hz, 1H), 7.20 (d,J=3.7 Hz, 1H), 7.46 (br, 2H), 7.97 (m, 1H), m.p.; 148-152° C.

EXAMPLE 251-{2-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.98 (m, 8H), 3.88 (s,3H), 4.20 (m, 1H), 6.77 (dd, J=1.6 Hz, 3.5 Hz, 1H), 7.23 (d, J=3.5 Hz,1H), 7.99 (d, J=1.6 Hz, 1H). 6.77 (dd, J=1.6 Hz, 3.5 Hz, 1H), 7.23 (d,J=3.5 Hz, 1H), 7.99 )d, J=1.6 Hz, 1H). m.p.; 168-172° C.

EXAMPLE 261-{2-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.21-1.34 (m, 1H), 1.43-1.70(m, 7H), 1.82-1.90 (m, 2H), 3.90 (s, 3H), 6.78-6.81 (m, 1H, 7.25-7.28(m, 1H), 8.01-8.03 (m, 1H). FAB MS; 338 (M⁺+1).

EXAMPLE 274-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.48 (s, 6H), 3.90 (s, 3H),6.78-6.81 (m, 1H), 7.22-7.28 (m, 1H), 8.00-8.03 (m, 1H). ESI MS; 298.1(M⁺+1).

EXAMPLE 281-{2-[6-Amino-8-(2-furyl)-9-phenyl-9H-2-purinyl]-1-ethynyl}-1cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-1.72 (m, 4H), 1.77-1.90(m, 4H), 6.04 (d, J=3.3 Hz, 1H), 6.53 (dd, J=1.9,3.3 Hz, 1H), 7.48-7.50(m, 2H), 7.61-7.63 (m, 3H), 7.81 (d, J=1.9 Hz, 1H. 6.04 (d, J=3.3 Hz,1H), 6.53 (dd, J=1.9,3.3 Hz, 1H) 7.48-7.50 (m, 2H), 7.61-7.63 (m, 3H),7.81 (d, J=1.9 Hz, 1H). FAB MS; 386 (M⁺+1).

EXAMPLE 291-[6-Ethoxy-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-3-ol

NMR (400 MHz, δ, δ, CDCl₃;) 1.13 ((dd, J=6.8 and 1.6 Hz, 6H), 1.52 (t,J=7.1 Hz, 1H), 4.70 (q, J=7.1 Hz, 2H), (dd, J=6.8 and 1.6 Hz, 6H), 1.52(t, J=7.1 Hz, 1H), 4.70 (q, J=7.1 Hz, 2H), 6.62-6.64 (m, 1H), 7.33-7.35(m, 1H), 7.64-7.66 (m, 1H). FAB MS; 341 (M⁺+1).

EXAMPLE 301-{2-6-Amino-9-methyl-8-phenyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.32 (m, 1H), 1.44-1.66(m, 7H), 1.81-1.88 (m, 2H), 3.79 (s, 3H), 7.57-7.60 (m, 3H), 7.85-7.88(m, 2H). FAB MS; 348 (M⁺+1).

EXAMPLE 311-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.45-1.66(m, 7H), 1.83-1.86 (m, 2H), 3.78 (s, 3H), 7.40-7.45 (m, 1H), 7.60-7.66(m, 1H), 7.69-7.72 (m, 2H). FAB MS; 366. (M⁺+1). m.p.; 230-232° C.

EXAMPLE 321-{2-[6-Amino-9-methyl-8-(2-thienyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.42-1.70 (m, 10H), 3.88 (s,3H), 7.26-7.29 (m, 1H), 7.80-7.83 (m, 2H). m.p.; 171-175° C.

EXAMPLE 332-(4-Cyclohexyl-1-butynyl)-8-(2-furyl)-9-methyl-9H-6-purinamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.82-0.96 (m, 2H), 1.08-1.24(m, 3H), 1.30-1.50 (m, 3H), 1.58-1.76 (m, 5H), 2.48 (t, J=7.3 Hz, 2H),3.88 (s, 3H), 6.78 (dd, J=1.8 Hz, 3.7 Hz, 1H), 7.25 (d, J=3.7, 1H), 2.48(t, J=7.3 Hz, 2H), 3.88 (s, 3H), 6.78 (dd, J=1.8 Hz, 3.7 Hz, 1H), 7.25(d, J=3.7, 1H), 8.00 (m, 1H). m.p.; 165-169° C.

EXAMPLE 341-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.97 (t, J=6.8 Hz, 6H), δ, DMSO-d ₆); 0.97(t, J=6.8 Hz, 6H), 1.78-1.83 (m, 1H), 3.88 (s, 3H), 4.22 (d, J=6.4 Hz,1H), 4.22 (d, J=6.4 Hz, 1H), 6.78-6.79 (m, 1H), 7.20-7.23 (m, 1H), 7.99(s, 1H). FAB MS; 312 (M⁺+1).

EXAMPLE 351-[2-(6-Amino-8-cyclohexyl-9-methyl-9H-2-purinyl)-1-ethynyl]-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 2H), 1.35-1.77(m, 12H), 1.78-1.86 (m, 4H), 1.93-2.00 (m, 2H), 3.07-3.17 (m, 1H), 3.73(s, 3H). FAB MS; 354 (M⁺+1).

EXAMPLE 362-(2-Cyclohexyl-1-ethynyl)-8-(2-furyl)-9-methyl-9H-6-purinamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.24-1.88 (m, 8H), 2.60-2.74(m, 1H), 3.88 (s, 3H), 6.78 (br, 1H), *7.25 (d, J=3.3, 1H), 7.25 (d,J=3.3, 1H), 8.00 (br, 1H). m.p.; 155-160° C.

EXAMPLE 371-}2-[6-Amino-9-methyl-8-(2-pyridinyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.22-1.33 (m, 1H), 1.46-1.71(m, 7H), 1.84-1.94 (m, 2H), 4.13 (s, 3H), 7.58-7.61 (m, 1H), 8.05-8.10(m, 1H), 8.26-8.28 (m, 1H), 8.77-8.79 (m, 1H). FAB MS; 349 (M⁺+1).

EXAMPLE 381-{2-[6-Amino-8-(4-chlorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.19-1.30 (m, 1H), 1.42-1.65(m, 7H), 1.80-1.88 (m, 2H), 3.77 (s, 3H), 7.64 (d, J=8.0 Hz, 2H), 7.88(d, J=8.0 Hz, 2H). 7.64 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H). FABMS; 382 (M⁺+1) FAB.

EXAMPLE 391-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-3-isopropyl-4-methyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.96 (d, J=7.0 Hz, 6H), 1.01 (d, J=7.0 Hz,6H), δ, DMSO-d ₆); 0.96 (d, J=7.0 Hz, 6H), 1.01 (d, J=7.0 Hz, 6H),1.86-1.94 (m, 2H), 3.87 (s, 3H), 6.78-6.80 (m, 1H), 7.22-7.26 (m, 1H),8.01 (s, 1H). FAB MS; 354 (M⁺+1).

EXAMPLE 401-[2-(6-Amino-9-benzo[b]furan-2-yl-9-methyl-9H-2-purinyl)-1-ethynyl]-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.68 (m, 8H), 1.80-1.88(m, 2H), 3.99 (s, 3H), 7.32-7.46 (m, 2H), 7.66-7.81 (m, 3H). FAB MS; 388(M⁺+1).

EXAMPLE 418-(2-Furyl)-9-methyl-2-[3-morpholino-1-propynyl)-9H-purinamine

NMR (400 MHz, δ, δ, CDCl₃); 2.70 (t, J=5.0 Hz,4H), 3.78 (t, J=5.0Hz,4H), 2.70 (t, J=5.0 Hz,4H), 3.78 (t, J=5.0 Hz,4H), 3.79 (s, 2H), 4.02(s, 3H), 5.99 (br s, 2H), 6.62-6.65 (m, 1H), 7.10-7.13 (m, 1H),7.65-7.68 (m, 1H). FAB MS; 339 (M⁺+1).

EXAMPLE 421-{2-[6-Amino-8-(3-fluorophenyl-4-methoxyphenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.42-1.68(m, 7H), 1.80-1.88 (m, 2H), 3.79 (s, 3H), 3.92 (m, 3H), 7.34-7.39 (m,1H), 7.66-7.76 (m, 2H). FAB MS; 396 (M⁺+1).

EXAMPLE 432-(3-Amino-4-methyl-7-1-pentynyl)-8-(2-furyl)-9-methyl-9H-6-purinamineDihydrochloride

NMR (400 MHz; δ, d₆-DMSO); 1.05 (t, J=7.0 Hz, 6H), δ, DMSO-d ₆); 1.05(t, J=7.0 Hz, 6H), 2.12-2.20 (m, 1H), 3.88 (s, 3H), 4.25-4.30 (m, 1H),6.78-6.80 (m, 1H), 7.22-7.24 (m, 1H), 8.00 (s, 1H), 8.72 (br s, 2H). FABMS; 311 (M⁺+1).

EXAMPLE 444-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-tetrahydro-2H-4-pyranolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.66-1.75 (m, 2H), 1.83-1.92(m, 2H), 3.54-3.59 (m, 2H), 3.74-3.79 (m, 2H), 3.79 (s, 3H), 7.39-7.43(m, 1H), 7.60-7.72 (m, 3H). FAB MS; 368 (M⁺+1).

EXAMPLE 45 Ethyl3-{6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}benzoateHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.33 (t,J=7.1 Hz, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.44-1.68 (m, 7H), 1.82-1.89 (m,2H), 3.82 (s, 3H), 4.35 (q, J=7.1 Hz, 2H), 7.74 (t, J=7.7 Hz, 1H),8.12-8.17 (m, 2H), 8.44 (d, J=0.7 Hz, 1H). 4.35 (q, J=7.1 Hz, 2H), 7.74(t, J=7.7 Hz, 1H), 8.12-8.17 (m, 2H), 8.44 (d, J=0.7 Hz, 1H). FAB MS;420 (M⁺+1).

EXAMPLE 462-(3,3-Diphenyl-1-butynyl)-8-(3-fluorophenyl)-9-methyl-9H-6-purinylamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.79 (s, 1H), 7.24-7.28 (m,2H), 7.33-7.37 (m, 4H), 7.39-7.45 (m, 1H), 7.56-7.59 (m, 4H), 7.60-7.65(m, 1H), 7.69-7.73 (m, 2H). FAB MS; 450 (M⁺+1).

EXAMPLE 47 Ethyl2-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}acetate

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.17-1.37 (m, 1H), 1.21 (t,J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.46-1.76 (m, 7H), 1.99-2.14 (m,2H), 3.70 (br s, 2H), 4.19 (q, J=7.1 Hz, 2H), 4.19 (q, J=7.1 Hz, 2H),4.99 (s, 2H), 6.43 (br s, 2H), 7.17-7.26 (m, 1H), 7.34-7.51 (m, 3H).

EXAMPLE 481-{2-[6-Amino-8-(3-fluorophenyl)-9-(2-methoxyethyl)-9H-9-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.42-1.67(m, 7H), 1.82-1.88 (m, 2H), 3.07 (s, 3H), 3.62 (t, J=5.3 Hz, 2H), 4.40(t, J=5.3 Hz, 2H), 3.62 (t, J=5.3 Hz, 2H), 4.40 (t, J=5.3 Hz, 2H),7.40-7.46 (m, 1H), 7.59-7.65 (m, 1H), 7.68-7.74 (m, 2H). FAB M; 410(M⁺+1).

EXAMPLE 491-2-[6-Amino-8-(3-fluorophenyl)-9-(2-hydroxyethyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.21-1.32 (m, 1H), 1.42-1.68(m, 7H), 1.81-1.89 (m, 2H), 3.73 (t, J=5.3 Hz, 2H), 4.28 (t, J=5.3 Hz,2H), 3.73 (t, J=5.3 Hz, 2H), 4.28 (t, J=5.3 Hz, 2H), 7.40-7.45 (m, 1H),7.59-7.65 (m, 1H), 7.73-7.79 (m, 2H). FAB MS; 396 (M⁺+1).

EXAMPLE 503-(6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}benzonitrileHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.40-1.70(m, 7H), 1.80-1.84 (m, 2H), 3.80 (s, 3H), 7.78 (t, J=7.8 Hz, 1H), 8.02(d, J=7.8 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 8.02(d, J=7.8 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.32 (s, 1H). FAB MS; 373(M⁺+1).

EXAMPLE 511-[2-[6-Amino-8-(3-chlorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.42-1.64(m, 7H), 1.80-1.89 (m, 2H), 3.79 (s, 3H), 7.54-7.60 (m, 2H), 7.82-7.85(m, 1H), 7.92 (br, 1H). FAB MS; 382 (M⁺+1). m.p.; 194-199° C.

EXAMPLE 521-{2-[6-Amino-9-methyl-8-[3-(trifluoromethyl)phenyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.42-1.70(m, 7H), 1.80-1.89 (m, 2H), 3.81 (s, 3H), 7.82 (t, J=11.0 Hz, 1H), 7.93(d, J=11.0 Hz, 1H), 8.19 (d, J=11.0 Hz, 1H), 7.82 (t, J=11.0 Hz, 1H),7.93 (d, J=11.0 Hz, 1H), 8.19 (d, J=11.0 Hz, 1H), 8.21 (s, 1H). FAB MS;416 (M⁺+1).

EXAMPLE 531-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.18-1.30 (m, 1H), 1.42-1.68(m, 7H), 1.81-1.90 (m, 2H), 3.82 (s, 3H), 7.49-7.54 (m, 1H), 7.58-7.64(m, 2H). FAB MS; 384 (M⁺+1).

EXAMPLE 54 1-{2-[6-Amino-9-methyl-8-(3-methylphenyl)-9H-2-purinylp9-1-ethynyl}-1-cyclohexanol Hydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.08-1.31 (m, 1H), 1.42-1.71(m, 7H), 1.82-1.92 (m, 2H), 2.40 (s, 3H), 3.81 (s, 3H), 7.41 (d, J=7.6Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.69 (s, 1H).FAB MS; 362 (M⁺+1).

EXAMPLE 551-{2-[6-Amino-8-(3-fluorophenyl)-9-(3-methoxyphenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.44-1.68(m, 7H), 1.83-1.91 (m, 2H), 3.83 (s, 3H), 7.18-7.20 (m, 1H), 7.41-7.42(m, 1H), 7.43-7.46 (m, 1H), 7.51-7.55 (m, 1H). FAB MS; 378 (M⁺+1).

EXAMPLE 561-{2-[6-Amino-8-(4-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclophexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.43-1.68(m, 7H), 1.81-1.89 (m, 2H), 3.79 (s, 3H), 7.42-7.47 (m, 2H), 7.90-7.96(m, 2H). FAB MS; 366 (M⁺+1).

EXAMPLE 571-{2-[6-Amino-8-(3-dimethylamino)phenyl]-9-methyl-9H-2-purinyl}-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.18-1.30 (m, 1H), 1.42-1.70(m, 7H), 1.80-1.92 (m, 2H), 3.05 (s, 6H), 3.85 (s, 3H), 7.32-7.70 (m,4H). FAB MS; 391 (M⁺+1).

EXAMPLE 581-{2-Amino-9-cyclopentyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethylnyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.40-1.64(m, 9H), 1.80-1.84 (m, 2H), 1.90-2.04 (m, 4H), 2.26-2.38 (m, 2H),4.60-4.74 (m, 1H), 7.40-7.50 (m, 3H), 7.58-7.64 (m, 1H). FAB MS; 420(M⁺+1). m.p.; 196-200° C.

EXAMPLE 591-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.32 (m, 1H), 1.42-1.66(m, 7H), 1.80-1.86 (m, 2H), 3.58 (s, 3H), 7.39-7.48 (m, 2H), 7.63-7.72(m, 2H). FAB MS; 366 (M⁺+1). m.p.; 151-155° C.

EXAMPLE 608-(3-Fluorophenyl)-9-methyl-2-[2-(3-pyridinyl)-1-ethynyl]-9H-6-purinamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.81 (s, 3H), 7.40-7.51 (m,2H), 7.60-7.76 (m, 4H), 7.90 (dt, J=7.8 7.90 (dt, J=7.8 and 1.6 Hz, 1H),8.64-8.67 (m, 1H). FAB MS; 345 (M⁺+1).

EXAMPLE 613-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}phenylHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.13 (s, 1H), 3.81 (s, 3H),6.85-6.89 (m, 1H), 6.93-6.96 (m, 1H), 7.00-7.05 (m, 1H), 7.25 (t, J=8.0Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.39-7.46 (m, 1H), 7.59-7.80 (m, 3H).FAB MS; 360 (M⁺+1).

EXAMPLE 621-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyl-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.97 (dd, J=6.8 Hz, 7.7 Hz, 6H), δ, DMSO-d₆); 0.97 (d, J=6.8 Hz, 7.7 Hz, 6H), 1.78-1.86 (m, 1H), 3.80 (s, 3H),4.24 (dd, J=6.1 Hz, 1H), 4.24 (d, J=6.1 Hz, 1H), 7.40-7.45 (m, 1H),7.60-7.66 (m, 1H), 7.69-8.30 (m, 2H). FAB MS; 340 (M⁺+1). m.p.; 170-173°C.

EXAMPLE 631-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.97 (t, J=7.5 Hz, 3H), δ, DMSO-d ₆); 0.97(t, J=7.5 Hz, 3H), 1.62-1.70 (m, 1H), 3.80 (s, 3H), 7.40-7.45 (m, 1H),7.60-7.66 (m, 1H), 7.69-7.76 (m, 2H). FAB MS; 326 (M⁺+1).

EXAMPLE 644-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.47 (s, 6H), 3.81 (s, 3H),7.40-7.47 (m, 1H), 7.60-7.67 (m, 1H), 7.69-7.74 (m, 2H). FAB MS; 326(M⁺+1). m.p.; 181-182° C.

EXAMPLE 651-{2-[6-Amino-8-(3-fluorophenyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.40-1.70(m, 7H), 1.82-1.94 (m, 2H), 5.70 (s, 1H), 7.42-7.50 (m, 1H), 7.60-7.70(m, 1H), 8.00-8.14 (m,2H). FAB MS; 353 (M⁺+1).

EXAMPLE 661-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.70 (t, J=7.3 Hz, 3H), δ, DMSO-d ₆); 0.70(t, J=7.3 Hz, 3H), 1.20-1.31 (m, 1H), 1.42-1.68 (m, 9H), 1.81-1.88 (m,2H), 4.22 (t, J=7.3 Hz, 3H), 4.22 (t, J=7.3 Hz, 3H), 7.41-7.47 (m, 1H),7.61-7.67 (m, 3H). FAB MS; 394 (M⁺+1).

EXAMPLE 671-{2-[6-Amino-8-(3-fluorophenyl)-9-isopropyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.31 (m, 1H), 1.42-1.68(m, 7H), 1.59 (d, J=6.8 Hz, 6H), 1.82-1.91 (m, 2H), 4.61 (sept, J=6.8Hz, 1H), 1.59 (d, J=6.8 Hz, 6H), 1.82-1.91 (m, 2H), 4.61 (sept, J=6.8Hz, 1H), 7.45-7.54 (m, 3H), 7.45-7.54 (m, 3H), 7.63-7.68 (m, 1H). FABMS; 394 (M⁺+1).

EXAMPLE 68N¹-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.91 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.91(t, J=7.2 Hz, 3H), 1.20-1.32 (m, 7H), 1.78-1.87 (m, 4H), 1.93 (t, J=7.1Hz, 2H), 2.94 (dq, J=5.5, 7.2 Hz, 2H), 4.25 (t, J=7.1 Hz, 2H), 1.93 (t,J=7.1 Hz, 2H), 2.94 (dq, J=5.5,7.2 Hz, 2H), 4.25 (t, J=7.1 Hz, 2H),7.40-7.45 (m, 1H), 7.58-7.65 (m, 3H), 7.72 (t, J=5.5 Hz, 1H). 7.72 (t,J=5.5 Hz, 1H). FAB MS; 465 (M⁺+1).

EXAMPLE 69N¹-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]propaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.90 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.90(t, J=7.2 Hz, 3H), 1.18-1.33 (m, 1H), 1.42-1.68 (m, 7H), 1.80-1.88 (m,2H), 2.55 (t, J=7.5 Hz, 2H), 2.93 (dq, J=5.5, 7.2 Hz, 2H), 4.43 (t,J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H), 2.93 (dq, J=5.5,7.2 Hz, 2H), 4.43(t, J=7.5 Hz, 2H), 7.39-7.45 (m, 1H), 7.58-7.66 (m, 3H), 7.90 (t, J=5.5Hz, 1H). 7.90 (t, J=5.5 Hz, 1H). FAB MS; 451 (M⁺+1).

EXAMPLE 701-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purionyl]-3-isopropyl-4-methyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.98 (d, J=6.8 Hz, 6H), 1.04 (d, J=6.8 Hz,6H), δ, DMSO-d ₆); 0.98 (d, J=6.8 Hz, 6H), 1.04 (d, J=6.8 Hz, 6H),1.87-1.97 (m, 2H), 3.83 (s, 3H), 7.41-7.48 (m, 1H), 7.62-7.70 (m, 1H),7.71-7.77 (m, 2H). FAB MS; 382 (M⁺+1).

EXAMPLE 71N¹-Isopropyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.94 (d, J=7.6 Hz, 6H), δ, DMSO-d ₆); 0.94(d, J=7.6 Hz, 6H), 1.20-1.32 (m, 1H), 1.41-1.68 (m, 7H), 1.78-1.88 (m,4H), 1.92 (t, J=7.1 Hz, 2H), 3.64-3.74 (m, 1H), 4.25 (t, J=7.6 Hz, 2H),1.92 (t, J=7.1 Hz, 2H), 3.64-3.74 (m, 1H), 4.25 (t, J=7.6 Hz, 2H),7.40-7.46 (m, 1H), 7.58-7.65 (m, 3H). FAB MS; 479 (M⁺+1).

EXAMPLE 72N¹-Ethyl-2-{6-amino-8-(3-fluorophenyl-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.98 (d, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.98(t, J=7.2 Hz, 3H), 1.18-1.30 (m, 1H), 1.40-1.68 (m, 7H), 1.65 (t, J=7.3Hz, 3H), 1.78-1.88 (m, 2H), 3.08 (dq, J=5.3, 7.2 Hz, 2H), 5.08 (q, J=7.3Hz, 1H), 1.65 (t, J=7.3 Hz, 3H), 1.78-1.88 (m, 2H), 3.08 (dq, J=5.3,7.2Hz, 2H), 5.08 (q, J=7.3 Hz, 1H), 7.39-7.48 (m, 3H), 7.58-7.63 (m, 1H),8.05 (t, J=5.3 Hz, 1H). 8.05 (t, J=5.3 Hz, 1H). FAB MS; 451 (M⁺+1).

EXAMPLE 731-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.00 (t, J=7.2 Hz, 6H), δ, DMSO-d ₆); 1.00(t, J=7.2 Hz, 6H), 1.61-1.71 (m, 4H), 3.81 (s, 3H), 7.40-7.44 (m,1H),7.61-7.67 (m, 1H), 7.69-7.74 (m, 2H). FAB MS; 354 (M⁺+1).

EXAMPLE 74N¹-Ethyl-2-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]-2-phenylacetamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.00 (t, J=7.1 Hz, 3H), δ, DMSO-d₆); 1.00 (t,J=7.1 Hz, 3H), 1.19-1.30 (m, 1H), 1.40-1.68 (m, 7H), 1.78-1.88 (m, 2H),3.09-3.20 (m, 2H), 6.47 (s, 1H), 7.00-7.04 (m, 2H), 7.13-7.24 (m, 6H),7.29-7.35 (m, 1H), 8.39 (t, J=5.4 Hz, 1H). 8.39 (t, J=5.4 Hz, 1H). FABMS; 513 (M⁺+1).

EXAMPLE 758-(3-Fluorophenyl)-2-(3-methoxy-3-methyl-1-butynyl)-9-methyl-9H-6-purinamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.50 (s, 6H), 3.34 (s, 3H),3.83 (s, 3H), 7.41-7.48 (m, 1H), 7.60-7.68 (m, 1H), 7.70-7.76 (m, 2H).FAB MS; 340 (M⁺+1).

EXAMPLE 76N-{3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2-propynyl}-N′-ethylureaHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.25 (t, J=7.0 Hz, 3H), δ, DMSO-d ₆); 1.25(t, J=7.0 Hz, 3H), 1.68 (s, 6H), 3.46 (q, J=7.0 Hz, 2H), 3.46 (q, J=7.0Hz, 2H), 3.98 (s, 3H), 6.32 (s, 1H), 7.45-7.52 (m, 1H), 7.64-7.83 (m,2H). FAB MS; 396 (M⁺+1).

EXAMPLE 771-{2-(6-Amino-8-(3-fluorophenyl)-9-isobutyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.63 (d, J=6.6 Hz, 6H), δ, DMSO-d ₆); 0.63(d, J=6.6 Hz, 6H), 1.19-1.33 (m, 1H), 1.40-1.67 (m, 9H), 1.79-1.91 (m,3H), 4.13 (t, J=7.5 Hz, 2H), 4.13 (t, J=7.5 Hz, 2H), 7.38-7.45 (m, 1H),7.58-7.68 (m, 3H). FAB MS; 408 (M⁺+1).

EXAMPLE 782-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1ethynyl]-9H-9-purinyl}ethyloxyN-Ethyl-carbamate Hydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.86 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.86(t, J=7.2 Hz, 3H), 1.19-1.32 (m, 1H), 1.41-1.70 (m, 7H), 1.80-1.92 (m,2H), 2.80 (dq, J=5.5, 7.2 Hz, 2H), 4.19 (t, J=5.7 Hz, 2H). 4.44-4.52 (m,2H), 6.96 (t, J=5.5 Hz, 1H), 2.80 (dq, J=5.5,7.2 Hz, 2H), 4.19 (t, J=5.7Hz, 2H), 4.44-4.52 (m, 2H), 6.96 (t, J=5.5 Hz, 1H), 7.40-7.48 (m, 1H),7.58-7.66 (m, 3H). FAB MS; 467 (M⁺+1).

EXAMPLE 791-{2-[6-Amiono-8-(3-fluorophenyl)-9-phenethyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.25-1.72 (m, 8H), 1.87-1.90(m, 2H), 2.97 (t, J=6.0 Hz, 2H), 4.52 (t, J=6.0 Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 4.52 (t, J=6.0 Hz, 2H), 6.81-6.85 (m, 2H), 7.10-7.21 (m, 4H).FAB MS; 456 (M⁺+1).

EXAMPLE 80N¹-Ethyl-3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-purinyl]-1-propanesulfonamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.93-1.00 (m, 3H), 1.19-1.32(m, 1H), 1.40-1.68 (m, 7H), 1.77-1.90 (m, 2H), 1.95-2.14 (m, 2H),2.75-2.87 (m, 2H), 2.90-2.98 (m, 2H), 4.35-4.42 (m, 2H), 6.94-7.02 (m,1H), 7.40-7.48 (m, 1H), 7.58-7.78 (m, 3H). FAB MS; 501 (M⁺+1).

EXAMPLE 811-{2-[6-Amino-8-(3-fluorophenyl)-9-(2-hydroxypropyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.00-1.10 (m, 3H), 1.18-1.33(m, 1H), 1.40-1.70 (m, 7H), 1.78-1.90 (m, 2H), 4.00-4.12 (m, 2H),4.12-4.21 (m, 1H), 7.36-7.43 (m,1H), 7.56-7.63 (m, 1H), 7.71-7.80 (m,2H). FAB MS; 410 (M⁺+1).

EXAMPLE 821-{2-[6-Amino-9-(2-butynyl)-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.68 (m, 8H), 1.75 (t,J=2.0 Hz, 3H), 1.80-1.88 (m, 2H), 5.00 (q, J=2.0 Hz, 2H), 1.75 (t, J=2.0Hz, 3H), 1.80-1.88 (m, 2H), 5.00 (q, J=2.0 Hz, 2H), 7.40-7.45 (m, 1H),7.62-7.78 (m, 3H). FAB MS; 404 (M⁺+1).

EXAMPLE 831-{2-[6-Amino-8-(3-fluorophenyl)-9-(3-morpholinopropyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.19-1.29 (m, 1H), 1.40-1.64(m, 7H), 1.79-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.84-3.08 (m, 4H),3.23-3.34 (m, 2H), 3.65-3.78 (m, 2H), 3.82-3.92 (m, 2H), 4.28-4.36 (m,2H), 7.42-7.48 (m, 1H), 7.60-7.68 (m, 3H). FAB MS; 479 (M⁺+1).

EXAMPLE 841-{3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl-9H-9-purinyl}propyl}2-pyrrolidinoneHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.22-1.34 (m, 1H), 1.44-1.72(m, 7H), 1.78-1.93 (m, 6H), 2.14 (t, J=8.0 Hz, 2H), 3.08 (t, J=7.0 Hz,2H), 3.19 ) t, J=7.0 Hz, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.14 (t, J=8.0 Hz,2H), 3.08 (t, J=7.0 Hz, 2H), 3.19 (t, J=7.0 Hz, 2H), 4.22 (t, J=7.0 Hz,2H), 7.44-7.50 (m, 1H), 7.59-7.70 (m, 3H). FAB MS; 477 (M⁺+1).

EXAMPLE 851-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.44-1.66 (m, 8H), 1.76-1.84(m, 2H), 1.94-2.02 (m, 2H), 3.80 (s, 3H), 7.38-7.44 (m, 1H), 7.58-7.66(m, 1H), 7.64-7.44 (m, 2H). FAB MS; 380 (M⁺+1).

EXAMPLE 86N¹-Cyclopropyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.25-0.30 (m, 2H), 0.50-0.56(m, 2H), 1.20-1.34 (m, 1H), 1.40-1.70 (m, 7H), 1.78-1.94 (m, 6H),2.43-2.54 (m, 1H), 4.26 (t, J=7.0 Hz, 2H), 4.26 (t, J=7.0 Hz, 2H),7.41-7.47 (m, 1H), 7.60-7.68 (m, 3H), 7.81 (d, J=4.4 Hz, 1H). 7.81 (d,J=4.4 Hz, 1H). FAB MS; 477 (M⁺+1).

EXAMPLE 871-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-ethynyl}-4-methyl-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.89 (d, J=6.0 Hz, 3H), δ, DMSO-d ₆); 0.89(d, J=6.0 Hz, 3H), 1.25-1.53 (m, 5H), 1.63-1.74 (m, 2H), 1.89-1.98 (m,2H), 3.82 (s, 3H), 7.42-7.48 (m, 1H), 5.62-7.80 (m, 3H). FAB MS; 380(M⁺+1).

EXAMPLE 881-{9-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1,4-cyclohexanediolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.58-1.60 (m, 4H), 1.73-1.79(m, 2H), 1.93-1.99 (m, 2H), 3.14 (s, 1H), 3.47-3.53 (m, 1H), 3.83 (s,3H), 7.41-7.47 (m, 1H), 7.62-7.73 (m, 3H). FAB MS; 382 (M⁺+1).

EXAMPLE 891-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.74-1.85 (m, 2H), 2.16-2.27(m, 2H), 2.34-2.43 (m, 2H), 3.81 (s, 3H), 7.39-7.47 (m, 1H), 7.56-7.77(m, 3H). ESI MS; 338.0 (M⁺+1). m.p.; 198-199° C.

EXAMPLE 901-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.64-1.79 (m, 4H), 1.84-1.97(m, 4H), 3.82 (s, 3H), 7.48-7.54 (m, 1H), 7.57-7.64 (m, 2H). FAB MS; 370(M⁺+1). m.p.; 255-258° C.

EXAMPLE 911-{2-{6-Amino-9-methyl-8-[3-(trifluoromethyl)phenyl]-9H-2-purinyl}-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.78 (m, 4H), 1.82-1.96(m, 4H), 3.81 (s, 3H), 7.79-7.85 (m, 1H), 7.91-7.95 (m, 1H), 8.17-8.21(m, 2H). FAB MS; 402 (M⁺+1).

EXAMPLE 921-{2-[6-Amino-8-(3-fluorophenyl-9-(2-hydroxyethyl)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.72-1.80 (m, 4H), 1.84-1.98(m, 4H), 3.73 (t, J=5.6 Hz, 2H), 4.27 (t, J=5.6 Hz, 2H), 3.73 (t, J=5.6Hz, 2H), 4.27 (t, J=5.6 Hz, 2H), 7.38-7.45 (m, 1H), 7.58-7.64 (m, 1H),7.71-7.80 (m, 2H). FAB MS; 382 (M⁺+1).

EXAMPLE 931-{2-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.56-1.77 (m, 4H), 1.77-1.95(m, 4H), 3.60 (s, 3H), 7.45-7.63 (m, 3H). ESI MS; 370 (M⁺+1).

EXAMPLE 941-{2[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.64-1.79 (m, 4H), 1.83-1.96(m, 4H), 3.63 (s, 3H), 7.40-7.45 (m, 1H), 7.52-7.56 (m, 1H), 7.66-7.74(m, 1H). FAB MS; 371 (M⁺+1).

EXAMPLE 953-[6-Amino-2-[2-(1-hydroxycyclopenyl)-1-ethynyl]-9-methyl-9H-8-purinyl]phenolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.63-1.79 (m, 4H), 1.83-1.97(m, 4H), 3.76 (s, 3H), 6.94-6.98 (m, 1H), 7.21-7.27 (m, 2H), 7.37 (t,J=7.9 Hz, 1H). 7.37 (t, J=7.9 Hz, 1H). FAB MS; 350 (M⁺+1).

EXAMPLE 961-{2-[6-Dimethylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, δ, CDCl₃); 1.76-1.97 (m, 4H), 2.03-2.13 (m, 2H),2.13-2.22 (m, 2H), 2.22 (s, 1H), 3.58 (br s, 6H), 3.88 (s, 3H),7.17-7.23 (m, 1H), 7.46-7.57 (m, 3H).

EXAMPLE 971-{2-[8-(3-Fluorophenyl)-9-methyl-6-methylamino-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, δ, CDCl₃); 1.72-1.96 (m, 4H), 2.02-2.12 (m, 2H),2.14-2.22 (m, 2H), 2.26 (s, 1H), 3.25 (br s, 3H), 3.89 (s, 3H), 5.87 (brs, 1H), 7.20-7.25 (m, 1H), 7.44-7.56 (m, 3H).

EXAMPLE 981-{2-[6-Benzylamino-8-(3-fluorophenyl)-9-methyl-9H-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.64-1.80 (m, 4H), 1.86-1.97(m, 4H), 3.81 (s, 3H), 4.72 (br s, 2H), 7.20-7.25 (m, 1H), 7.28-7.37 (m,4H), 7.39-7.45 (m, 1H), 7.60-7.66 (m, 1H), 7.68-7.75 (m, 2H), 8.53 (brs, 1H).

EXAMPLE 991-{2-[8-(3-Fluorophenyl)-6-[(2-hydroxyethyl)amino]-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.65-1.82 (m, 4H), 1.84-2.02(m, 4H), 3.59 (br s,4H), 3.82 (s, 3H), 7.41-7.47 (m, 1H), 7.61-7.67 (m,1H), 7.70-7.76 (m, 2H), 7.98 (br s, 1H).

EXAMPLE 1001-{2-[6-Cyclopentylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.50-1.64 (m, 4H), 1.65-1.81(m, 6H), 1.82-2.00 (m, 6H), 3.80 (s, 3H), 4.55 (br s, 1H), 7.40-7.46 (m,1H), 7.61-7.67 (m, 1H), 7.70-7.75 (m, 2H), 8.06 (br s, 1H).

EXAMPLE 1013-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9H-9-purinyl}-1,2-propanediolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-1.80 (m, 4H), 1.82-1.98(m, 4H), 3.30-3.40 (m, 2H), 3.80-4.00 (m, 1H), 4.13 (dd, J=9.6,14.5 Hz,1H), 4.32 (dd, J=3.5,14.5 Hz, 1H), 4.13 (dd, J=9.6,14.5 Hz, 1H), 4.32(dd, J=3.5,14.5 Hz, 1H), 7.37-7.44 (m, 1H), 7.56-7.64 (m, 1H), 7.74-7.86(m, 2H). FAB MS; 412 (M⁺+1).

EXAMPLE 1024-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-methyl-4-piperidinolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 2.04-2.30 (m, 4H), 2.72 and2.81 (d×2,J=6.0 Hz, 3H), 2.81 (d×2,J=6.0 Hz, 3H), 3.05‥3.49 (m, 4H),3.80 and 3.82 (s×2,3H), 7.39-7.47 (m, 1H), 7.59-7.74 (m, 3H). FAB MS;381 (M⁺+1).

EXAMPLE 1031-{4-[2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]4-hydroxypiperidino}-1-ethanoneHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.50 and 1.93 (m, 4H),1.97-2.00 (s×2,3H), 3.14 and 3.79 (s×2, 3H), 3.25-3.69 (m, 4H),7.39-7.45 (m, 1H), 7.59-7.72 (m, 3H). FAB MS; 409 (M⁺+1).

EXAMPLE 1044-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-4-piperidinolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.95-2.18 (m, 4H), 3.02-3.20(m, 4H), 3.80 (s, 3H), 7.38-7.46 (m, 1H), 7.58-7.76 (m, 3H). FAB MS; 449(M⁺+1).

EXAMPLE 1052-{6-Amino-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9-methyl-9H-8-purinyl}-6-fluorophenolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-1.80 (m, 4H), 1.80-1.95(m, 4H), 3.66-3.73 (m, 3H), 6.94-7.03 (m, 1H), 7.35-7.47 (m, 2H). FABMS; 368 (M⁺+1).

EXAMPLE 1063-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-phenyl-2-propyn-1-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.77 (s, 3H), 5.60 (d, J=6.0Hz, 1H), 6.26 (d, J=6.0 Hz, 1H), 5.60 (d, J=6.0 Hz, 1H), 6.26 (d, J=6.0Hz, 1H), 7.29-7.33 (m, 1H), 7.36-7.43 (m, 3H), 7.47 (br s, 2H),7.50-7.53 (m, 2H), 7.58-7.64 (m, 1H), 7.66-7.71 (m, 2H). FAB MS; 374(M⁺+1).

EXAMPLE 1071-{2-[6-Amino-8-(3-fluoro-2-methylphenyl)-9-methyl-9H-2-purinyl]1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.79 (m, 4H), 1.83-1.96(m, 4H), 2.13 (d, J=2.0 Hz, 3H), 2.13 (d, J=2.0 Hz, 3H), 3.50 (s, 3H),7.33-7.42 (m, 3H). FAB MS; 366 (M⁺+1).

EXAMPLE 1081-{2-[6-Amino-9-methyl-8-(1,3-thiazol-2-yl)-9H-2-purinyl]-1-ethynyl}-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.61-1.78 (m, 4H), 1.81-1.97(m, 4H), 4.09 (s, 3H), 7.99 (d, J=3.2 Hz, 1H), 8.11 (d, J=3.2 Hz, 1H).7.99 (d, J=3.2 Hz, 1H), 8.11 (d, J=3.2 Hz, 1H). FAB MS; 341 (M⁺+1).

EXAMPLE 109N¹-Ethyl-(1R,3R)-3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]9H-9-purinyl}cyclopentanone-1-carboxamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.01(t, J=7.2 Hz, 3H), 1.64-2.22 (m, 12H), 2.44-2.68 (m, 2H), 3.08 (dq,J=2.7, 7.2 Hz, 2H),1Θ 3.08 (dq, J=2.6, 7.2 Hz, 2H), 4.60-4.71 (m, 1H),7.43-7.49 (m, 1H), 7.50-7.55 (m, 2H), 7.61-7.68 (m, 1H), 7.83 (t, J=2.6Hz, 1H). 7.83 (t, J=2.6 Hz, 1H).

EXAMPLE 1101-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purionyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.76-1.86 (m, 2H), 2.20-2.32(m, 2H), 2.36-2.46 (m, 2H), 3.85 (s, 3H), 7.46-7.55 (m, 1H), 7.56-7.67(m, 2H). FAB MS; 356 (M⁺+1).

EXAMPLE 1111-{2-[-6-Amino-9-cyclopropyl-8-(3-fluorophenyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.67-0.72 (m, 2H), 1.01-1.07(m, 2H), 1.62-1.80 (m, 4H), 1.84-1.97 (m, 4H), 3.65-3.73 (m, 1H),7.36-7.42 (m, 1H), 7.75-7.81 (m, 2H). FAB MS; 378 (M⁺+1).

EXAMPLE 1128-(3-Fluorophenyl)-9-methyl-2-(3-phenyl-1-propynyl)-9H-6-purinamineHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.79 (s, 3H), 3.91 (s, 2H),7.24-7.29 (m, 1H), 7.34-7.44 (m, 5H), 7.59-7.65 (m, 1H), 7.67-7.72 (m,2H). FAB MS; 358 (M⁺+1).

EXAMPLE 1131-{2-[8-(3,5-Difluorophenyl)-9-methyl-6-(phenethylamino)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-1.78 (m, 4H), 1.78-1.98(m, 4H), 2.93 (t, J=7.2 Hz, 2H), 2.93 (t, J=7.2 Hz, 2H), 3.60-3.75 (m,2H), 3.80 (s, 3H), 7.14-7.21 (m, 1H), 7.22-7.32 (m, 4H), 7.44-7.52 (m,1H), 7.54-7.64 (m, 2H), 8.05-8.12 (m, 1H). FAB MS; 474 (M⁺+1).

EXAMPLE 1141-{2-[8-(3,5-Difluorophenyl)-9-methyl-6-methylamino-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, δ, CDCl₃); 1.75-1.94 (m 4H), 2.03-2.12 (m, 2H),2.12-2.22 (m, 2H), 3.25 (br s, 3H), 3.90 (s, 3H), 5.82 (br s, 1H),6.95-7.00 (m, 1H), 7.29-7.36 (m, 2H).

EXAMPLE 1151-{2-[6-Ethylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); 1.19 (d, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.19(t, J=7.2 Hz, 3H), 1.65-1.81 (m, 4H), 1.84-1.98 (m, 4H), 3.50 (br s,2H), 3.80 (s, 3H), 5.44 (s, 1H), 7.38-7.45 (m, 1H), 7.59-7.66 (m, 1H),7.67-7.73 (m, 2H), 7.95 (br s, 1H). FAB MS; 380 (M⁺+1).

EXAMPLE 1161-{2-[8-(3-Fluorophenyl)-9-methyl-6-propylamino-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); 0.91 (t, J=7.2 Hz, 3H), 1.62 (sex, J=7.2 Hz,2H), δ, DMSO-d ₆); 0.91 (t, J=7.2 Hz, 3H), 1.62 (sex, J=7.2 Hz, 2H),1.66-1.81 (m, 4H), 1.84-2.00 (m, 4H), 3.43 (br s, 2H), 3.80 (s, 3H),5.44 (s, 1H), 7.38-7.45 (m, 1H), 7.59-7.67 (m, 1H), 7.68-7.74 (m, 2H),7.91-7.98 (m, 1H). FAB MS; 394 (M⁺+1).

EXAMPLE 1171-{2-[8-(3-Fluorophenyl)-6-isobutylamino-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, δ, CDCl₃); 1.02 (d, J=6.8 Hz, 6H), 1.02 (d, J=6.8 Hz,6H), 1.68-1.92 (m, 4H), 1.97 (sept, J=6.8 Hz, 6H), 1.97 (sept, J=6.8 Hz,6H), 2.02-2.22 (m, 4H), 3.51 (br s, 2H), 3.88 (s, 3H), 5.89 (br s, 1H),7.18-7.25 (m, 1H), 7.45-7.57 (m, 1H), 7.45-7.57 (m, 3H). FAB MS; 408(M⁺+1).

EXAMPLE 1181-[2-(6-Amino-9-methyl-8-phenyl-9H-2-purinyl)-1-ethynyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.66-1.83 (m, 4H), 1.87-2.00(m, 4H), 3.83 (s, 3H), 7.59-7.65 (m, 3H), 7.86-7.92 (m, 2H). FAB MS; 334(M⁺+1).

EXAMPLE 1193-[6-Amino)-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-propyn-1-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.79 (s, 3H), 4.30 (s, 2H),7.38-7.44 (m, 1H), 7.59-7.65 (m, 1H), 7.66-7.72 (m, 2H).

EXAMPLE 120 1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl]-2-methoxy-1-cyclohexanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.13-2.00 (m, 8H), 3.07 (d,J=9.6,4.0 Hz, 1H), 3.07 (d, J=9.6,4.0 Hz, 1H), 3.39 (s, 3H), 3.80 (s,3H), 5.69 (s, 1H), 7.39-7.45 (m, 1H), 7.48 (br s, 2H), 7.60-7.75 (m,3H). ESI MS; 396 (M⁺+1). m.p.; 281-283° C.

EXAMPLE 1211-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-2-methoxy-1-cyclohexanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.12-1.92 (m, 8H), 3.20-3.25(m, 1H), 3.40 (s, 3H), 3.80 (s, 3H), 5.33 (s, 1H), 7.38-7.45 (m, 1H),7.48 (br s, 2H), 7.60-7.74 (m, 3H). ESI MS; 396 (M⁺+1). m.p.; 195-197°C.

EXAMPLE 1221-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-2-cyclopenten-1-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 2.00-2.12 (m, 1H), 2.30-2.38(m, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 5.78 (s, 1H), 5.80-5.84 (m, 1H),5.94-5.98 (m, 1H), 7.39-7.46 (m, 1H), 7.47 (br s, 2H), 7.59-7.74 (m,3H). ESI MS; 350 (M⁺+1). m.p.; 191-193° C.

EXAMPLE 1231-{2-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.74-1.88 (m, 2H), 2.18-2.30(m, 2H), 2.36-2.45 (m, 2H), 3.65 (m, 3H), 7.53-7.59 (m, 2H), 7.60-7.65(m, 1H). FAB MS; 356 (M⁺+1). m.p.; 149-152° C.

EXAMPLE 1241-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (t, J=7.2 Hz, 6H), δ, DMSO-d ₆); 1.01(t, J=7.2 Hz, 6H), 1.61-1.75 (m, 4H), 3.85 (s, 3H), 7.51-7.57 (m, 1H),7.60-7.67 (m, 2H). ESI MS; 372 (M⁺+1). m.p.; 207-210° C.

EXAMPLE 1251-{2-[6-Amino-9-methyl-8-(2,3,5-trifluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.65-1.82 (m, 4H), 1.83-1.98(m, 4H), 3.65 (m, 3H), 5.44 (s, 1H), 7.50-7.60 (m, 3H), 7.81-7.90 (m,1H). ESI MS; 388 (M⁺+1). m.p.; 214-217° C.

EXAMPLE 1261-{2-[6-Amino-9-methyl-8-(2,3,5-trifluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.73-1.86 (m, 2H), 2.17-2.27(m, 2H), 2.34-2.43 (m, 2H), 3.65 (s, 3H), 6.00 (S, 1H), 7.50-7.62 (m,3H), 7.81-7.90 (m, 1H). ESI MS; 374 (M⁺+1). m.p.; 231-234° C.

EXAMPLE 1271-{2-[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.73-1.86 (m, 2H), 2.17-2.27(m, 2H), 2.34-2.43 (m, 2H), 3.63 (s, 3H), 6.00 (S, 1H), 7.40-7.47 (m,1H), 7.52-7.60 (m, 3H), 7.66-7.74 (m, 1H). ESI MS; 356 (M⁺+1). m.p.;225-229° C.

EXAMPLE 1281-[-6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3,4-dimethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (dd, J=17.0 and 17.0,6H), δ, DMSO-d ₆);1.01 (dd, J=17.0 and 17.0,6H), 1.24 (br s, 1H), 1.41 (s, 3H), 1.73-1.86(m, 1H), 3.81 (s, 3H). ESI MS; 354.1 (M⁺+1). m.p.; 191-192° C.

EXAMPLE 1291-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purionyl]-3,4,4-trimethyl-1-pentyn-1-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.04 (s,9H), 1.44 (s, 3H), 3.83(s, 3H), 7.42-7.48 (m, 1H), 7.58-7.77 (m, 3H). ESI MS; 368.1 (M⁺+1).m.p.; 193-194° C.

EXAMPLE 1301-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-4-phenyl-1-cycloheanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-2.14 (m, 9H), 2.41-2.49(m, 1H), 3.81 (s, 3H), 7.16-7.76 (m, 8H). ESI MS; 442 (M⁺+1). m.p.;247-249° C.

EXAMPLE 1311-{2-[6-Amino-9-methyl-8-(5-methyl-2-furyl)-9H-2-purinyl]-1-ethynyl}-1-cycloheanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.60-1.80 (m, 4H), 1.82-1.99(m, 4H), 2.41 (s, 3H), 3.87 (s, 3H), 4.23 (br, 3H), 6.41 (s, 1H), 7.19(s, 1H). ESI MS; 38 (M⁺+1). m.p.; 184-186° C.

EXAMPLE 1321-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.72 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz,6H), δ, DMSO-d ₆); 0.72 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz, 6H),1.58-1.73 (m, 6H), 4.24 (t, J=7.6 Hz, 2H), 4.24 (t, J=7.6 Hz, 2H),7.42-7.49 (m, 1H), 7.63-7.69 (m, 3H). ESI MS; 382 (M⁺+1). m.p.; 144-147°C.

EXAMPLE 1331-{2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.29 (t, J=7.2 Hz, 3H, δ, DMSO-d ₆); 1.29 (t,J=7.2 Hz, 3H), 1.66-1.82 (m, 4H), 1.86-2.02 (m, 4H), 4.31 (q, J=7.2 Hz,2H), 4.31 (q, J=7.2 Hz, 2H), 7.46-7.52 (m, 1H), 7.64-7.72 (m, 3H). FABMS; 366 (M⁺+1). m.p.; 188-191° C.

EXAMPLE 1342-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1,2,3-propanetriolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.17 (s, 2H), 3.50 (d, J=10.8Hz, 2H), 3.55 (d, J=10.8 Hz, 2H), 3.50 (d, J=10.8 Hz, 2H), 3.55 (d,J=10.8 Hz, 2H), 3.82 (s, 3H), 7.40-7.47 (m, 1H), 7.61-7.75 (m, 3H). ESIMS; 358 (M⁺+1). m.p.; 233-235° C.

EXAMPLE 1351-{2-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.26 (t, J=18.0 Hz, 3H), δ, DMSO-d ₆); 1.26(t, J=18.0 Hz, 3H), 1.64-1.80 (m, 4H), 1.84-1.98 (m, 4H), 4.29 (q,J=18.0 Hz, 2H), 4.29 (q, J=18.0 Hz, 2H), 7.50-7.58 (m, 3H). ESI MS;384.0 (M⁺+1). m.p.; 217-218° C.

EXAMPLE 1361-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (t, J=18.0 Hz, 6H), 1.25 (t, J=18.0 Hz,3H), δ, DMSO-d ₆); 1.01 (t, J=18.0 Hz, 6H), 1.25 (t, J=18.0 Hz, 3H),1.58-1.74 (m, 4H), 4.30 (q, J=17.4 Hz, 2H), 4.30 (q, J=17.4 Hz, 2H),7.47-7.60 (m, 3H). ESI MS; 386.2 (M⁺+1). m.p.; 204-205° C.

EXAMPLE 1371-{2-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.62 (t, J=18.0 Hz, 3H), δ, DMSO-d ₆); 1.62(t, J=18.0 Hz, 3H), 1.76-1.88 (m, 2H), 2.18-2.29 (m, 2H), 2.36-2.44 (m,2H), 4.30 (q, J=18.0 Hz, 2H), 4.30 (q, J=18.0 Hz, 2H), 7.49-7.59 (m,3H). ESI MS; 370.0 (M⁺+1). m.p.; 234-235° C.

EXAMPLE 1384-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.25 (t, J=17.6 Hz, 3H), δ, DMSO-d ₆); 1.25(t, J=17.6 Hz, 3H), 1.48 (s, 6H), 4.29 (q, J=17.4 Hz, 2H), 4.29 (q,J=17.4 Hz, 2H), 7.49-7.58 (m, 3H). ESI MS; 358.0 (M⁺+1).

EXAMPLE 1391-{2-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.70-0.78 (m, 2H), 1.02-1.11(m, 2H), 1.64-1.82 (m, 4H), 1.84-1.99 (m, 4H), 3.67-3.74 (m, 1H),7.45-7.53 (m, 1H), 7.65-7.73 (m, 2H). ESI MS; 396.1 (M⁺+1). m.p.;265-266° C.

EXAMPLE 1401-{-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.70-0.78 (m, 2H), 1.02-1.11(m, 2H), 1.72-1.86 (m, 2H), 2.16-2.28 (m, 2H), 2.30-2.46 (m, 2H),3.65-3.74 (m, 1H), 7.43-7.53 (m, 1H), 7.64-7.74 (m, 2H). ESI MS; 382.1(M⁺+1). m.p.; 228° C.

EXAMPLE 1414-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.70-0.77 (m, 2H), 1.03-1.11(m, 2H), 1.48 (s, 6H), 3.66-3.76 (m, 1H), 7.44-7.53 (m, 1H), 7.65-7.73(m, 2H). ESI MS; 370.1 (M⁺+1). m.p.; 245° C.

EXAMPLE 1421-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-purinyl]-3-ethynyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.70-0.75 (m, 2H), 0.97-1.10(m, 8H), 1.60-1.79 (m, 4H), 3.67-3.73 (m, 1H), 7.39-7.45 (m, 1H),7.59-7.66 (m, 1H), 7.77-7.84 (m, 2H). FAB MS; 380 (M⁺+1). m.p.; 145-148°C.

EXAMPLE 1434-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.70-0.75 (m, 2H), 1.00-1.10(m, 2H), 1.49 (s, 6H), 3.67-3.73 (m, 1H), 7.38-7.45 (m, 1H), 7.59-7.66(m, 1H), 7.77-7.84 (m, 2H). ESI MS; 352 (M⁺+1). m.p.; 143-145° C.

EXAMPLE 1441-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethynyl-1-pentyn-8-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.72 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz,6H), δ, DMSO-d ₆); 0.72 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz, 6H),1.58-1.75 (m, 6H), 4.27 (t, J=7.6 Hz, 2H), 4.27 (t, J=7.6 Hz, 2H),7.48-7.58 (m, 3H). ESI MS; 400 (M⁺+1). m.p.; 183-184° C.

EXAMPLE 1451-{2-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.72 (t, J=7.6 Hz, 3H), δ, DMSO-d ₆); 0.72(t, J=7.6 Hz, 3H), 1.57-1.81 (m, 4H), 4.23 (t, J=7.6 Hz, 2H), 4.23 (t,J=7.6 Hz, 2H), 7.48-7.57 (m, 3H). ESI MS; 398 (M⁺+1). m.p.; 210-211° C.

EXAMPLE 1461-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.72-1.85 (m, 2H), 2.17-2.27(m, 2H), 2.34-2.43 (m, 2H), 3.60 (s, 3H), 6.00 (s, 1H), 7.38-7.59 (m,4H), 7.61-7.74 (m, 2H). ESI MS; 338 (M⁺+1). m.p.; 136-138° C.

EXAMPLE 1471-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.65-1.80 (m, 4H), 1.80-1.96(m, 4H), 3.59 (s, 3H), 5.47 (s, 1H), 7.41-7.49 (m, 4H), 7.64-7.74 (m,2H). ESI MS; 352 (M⁺+1). m.p.; 166-168° C.

EXAMPLE 1481-[6-Amino-9-methyl-8-(5-methyl-2-furyl)-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.99 (t, J=7.2 Hz, 6H), 1.62 (q, J=7.2 Hz,2H), 1.64 (q, J=7.2 Hz, 2H), δ, DMSO-d ₆); 0.99 (t, J=7.2 Hz, 6H), 1.62(q, J=7.2 Hz, 2H), 1.64 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 3.17 (s, 1H),3.86 (s, 3H), 6.41 (d, J=0.4 Hz, 1H), 7.18 (d, J=0.4 Hz, 1H). 6.41 (d,J=0.4 Hz, 1H), 7.18 (dd, J=0.4 Hz, 1H). ESI MS; 340 (M⁺+1). m.p.;229-230° C.

EXAMPLE 1491-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-1-ol

NMR (400 MHz, δ, d₆-DMSO); 0.98 (t, J=7.4 Hz, 6H), δ, DMSO-d ₆); 0.98(t, J=7.4 Hz, 6H), 1.58-1.68 (m, 4H), 3.57 (s, 3H), 5.29 (s, 1H),7.39-7.46 (m, 4H), 7.63-7.71 (m, 2H). ESI MS; 354 (M⁺+1). m.p.; 199-201°C.

EXAMPLE 1501-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.72-0.78 (m, 2H), 1.01 (t,J=7.2 Hz, 6H), 1.01 (t, J=7.2 Hz, 6H), 1.04-1.12 (m, 2H), 1.58-1.75 (m,4H), 3.67-3.77 (m, 1H), 7.46-7.54 (m, 1H), 7.65-7.73 (m, 2H). ESI MS;398.2 (M⁺+1). m.p.; 225° C.

EXAMPLE 1514-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.48 (s, 6H), 3.17 (s, 3H),7.46-7.66 (m, 3H). ESI MS; 344.0 (M⁺+1). m.p.; 237-238° C.

EXAMPLE 1521-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.01 (t, J=18 Hz, 6H), 1.60-1.74 (q, J=18Hz,4H), δ, DMSO-d ₆); 1.01 (t, J=18 Hz, 6H), 1.60-1.74 (q, J=18 Hz,4H),3.65 (s, 3H), 7.53-7.65 (m, 3H). ESI MS; 372.2 (M⁺+1). m.p.; 147-148° C.

EXAMPLE 1534-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.50 (s, 6H), 3.67 (s, 3H),7.54-7.68 (m, 3H). ESI MS; 344.0 (M⁺+1). m.p.; 177-178° C.

EXAMPLE 1544-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.25 (t, J=7.2 Hz, 3H), 1.49 (s, 6H), 4.10(q, J=7.2 Hz, 2H), δ, DMSO-d ₆); 1.25 (t, J=7.2 Hz, 3H), 1.49 (s, 6H),4.10 (q, J=7.2 Hz, 2H), 7.41-7.56 (m, 2H), 7.60-7.79 (m, 1H). ESI MS;358 (M⁺+1). m.p.; 213-215° C.

EXAMPLE 1551-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.00 (t, J=7.2 Hz, 6H), 1.22 (t, J=7.2 Hz,3H), 1.64 (q, J=7.2 Hz, 2H), 1.65 (q, J=7.2 Hz, 2H), 4.10 (q, J=7.2 Hz,2H), δ, DMSO-d ₆); 1.00 (t, J=7.2 Hz, 6H), 1.22 (t, J=7.2 Hz, 3H), 1.64(q, J=7.2 Hz, 2H), 1.65 (q, J=7.2 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H),7.42-7.57 (m, 2H), 7.69-7.78 (m, 1H). ESI MS: 386 (M⁺+1). m.p.; 222-224°C.

EXAMPLE 156 4-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.46 (s, 6H), 3.60 (s, 3H),5.60 (s, 1H), 7.41-7.54 (m, 4H), 7.64-7.74 (m, 2H). ESI MS; 326 (M⁺+1).m.p.; 198-199° C.

EXAMPLE 1571-{2-[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.23 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.23(t, J=7.2 Hz, 3H), 1.74-1.86 (m, 2H), 2.18-2.27 (m, 2H), 2.36-2.43 (m,2H), 4.09 (q, J=14.4 Hz, 2H), 4.09 (q, J=14.4 Hz, 2H), 7.42-7.47 (m,1H), 7.51-7.55 (m, 1H), 7.69-7.76 (m, 1H). ESI MS; 370 (M⁺+1). m.p.;139-142° C.

EXAMPLE 1581-{2-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.24 (t, J=7.0 Hz, 3H), δ, DMSO-d ₆); 1.24(t, J=7.0 Hz, 3H), 1.65-1.80 (m, 4H), 1.85-2.00 (s,4H), 4.05-4.15 (m,2H), 5.10 (s, 1H), 7.42-7.58 (m, 2H), 7.69-7.78 (m, 2H). ESI MS; 384(M⁺+1). m.p.; 138-140° C.

EXAMPLE 1594-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-1-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.71 (t, J=7.6 Hz, 3H), δ, DMSO-d ₆); 0.71(t, J=7.6 Hz, 3H), 1.49 (s, 6H), 1.57-1.68 (m, 2H), 4.25 (t, J=7.6 Hz,2H), 4.25 (t, J=7.6 Hz, 2H), 7.50-7.58 (m, 3H). ESI MS; 372 (M⁺+1).m.p.; 148-150° C.

EXAMPLE 1601-{2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.74 (bs, 2H), 1.02-1.11 (m,2H), 1.76-1.90 (m, 2H), 2.20-2.31 (m, 2H), 2.38-2.50 (m, 2H), 3.69-3.77(m, 1H), 7.41-7.48 (m, 1H), 7.60-7.67 (m, 1H), 7.79-7.86 (m, 2H). ESIMS; 364 (M⁺+1). m.p.; 167-170° C.

EXAMPLE 1611-{2-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.70 (t, J=7.6 Hz, 3H), 1.64 (tq, J=7.6 Hz,7.6 Hz, 2H), δ, DMSO-d ₆); 0.70 (t, J=7.6 Hz, 3H), 1.64 (tq, J=7.6 Hz,7.6 Hz, 2H), 1.67-1.83 (m, 2H), 2.23-2.32 (m, 2H), 2.39-2.50 (m, 2H),4.10 (t, J=7.6 Hz, 2H), 4.10 (t, J=7.2 Hz, 2H), 7.44-7.52 (m, 1 Hz),7.53-7.59 (m, 1H), 7.72-7.81 (m, 1H). ESI MS; 384 (M⁺+1). m.p.; 124-127°C.

EXAMPLE 1621-{2-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.69 (t, J=7.6 Hz, 3H), 1.63 (tq, J=7.6 Hz,7.6 Hz, 2H), δ, DMSO-d ₆); 0.69 (t, J=7.6 Hz, 3H), 1.63 (tq, J=7.6 Hz,7.6 Hz, 2H), 1.67-1.82 (m, 4H), 1.85-2.00 (m, 4H), 4.07 (t, J=7.6 Hz,2H), 4.07 (t, J=7.6 Hz, 2H), 7.43-7.50 (m, 1H), 7.50-7.59 (m, 1H),7.70-7.79 (m, 1H). ESI MS; 398 (M⁺+1). m.p.; 184-188° C.

EXAMPLE 1634-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyl-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.68 (t, J=7.6 Hz, 3H), 1.49 (s, 6H), 1.62(tq, J=7.6 Hz, 7.6 Hz, 2H), 4.07 (t, J=7.6 Hz, 2H), δ, DMSO-d ₆); 0.68(t, J=7.6 Hz, 3H), 1.49 (s, 6H), 1.62 (tq, J=7.6 Hz, 7.6 Hz, 2H), 4.07(t, J=7.6 Hz, 2H), 7.43-7.49 (m, 1H), 7.51-7.57 (m, 1H), 7.70-7.78 (m,1H). ESI MS; 372 (M⁺+1). m.p.; 230-233° C.

EXAMPLE 1641-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.68 (t, J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz,6H), 1.59-1.75 (m, 6H) 4.08 (t, J=7.6 Hz, 2H), δ, DMSO-d ₆); 0.68 (t,J=7.6 Hz, 3H), 1.01 (t, J=7.6 Hz, 6H), 1.59-1.75 (m, 6H), 4.08 (t, J=7.6Hz, 2H), 7.48-7.50 (m, 1H), 7.52-7.57 (m, 1H), 7.71-7.79 (m, 1H). ESIMS; 400 (M⁺+1). m.p.; 187-188° C.

EXAMPLE 1651-{2-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.67-0.72 (m, 2H), 0.89-0.97(m, 2H), 1.73-1.87 (m, 2H), 2.17-2.28 (m, 2H), 2.35-2.45 (m, 2H),3.37-3.47 (m, 1H), 7.49-7.56 (m, 2H), 7.59-7.66 (m, 1H). ESI MS: 382(M⁺+1). m.p.; 161-164° C.

EXAMPLE 1661-{2-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.66-0.73 (m, 2H), 0.89-0.97(m, 2H), 1.63-1.82 (m, 4H), 1.83-1.98 (m, 4H), 3.37-3.46 (m, 1H),7.49-7.56 (m, 2H), 7.59-7.66 (m, 1H). ESI MS: 396 (M⁺+1). m.p.; 230-232°C.

EXAMPLE 1674-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.65-0.73 (m, 2H), 0.88-0.98(m, 2H), 1.48 (s, 6H), 3.37-3.46 (m, 1H), 7.40-7.75 (br, 2H), 7.48-7.55(m, 2H), 7.59-7.65 (m, 1H). EST MS; 370 (M⁺+1). m.p.; 196-198° C.

EXAMPLE 1681-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopentyl-9H-2-purinyl]-3-ethyl-1-pentyl-3-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.66-0.73 (m, 2H), 0.89-0.97(m, 2H), 1.00 (t, J=7.2 Hz, 6H) 1.00 (t, J=7.2 Hz, 6H), 1.60-1.73 (m,4H), 3.39-3.46 (m, 1H), 7.49-7.56 (m, 2H), 7.59-7.65 (m, 1H). ESI MS;398 (M⁺+1). m.p.; 215-216° C.

EXAMPLE 1691-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.84 (t, J=7.2 Hz, 3H), 1.70-2.22 (m, 10H),4.37 (t, J=7.4 Hz, 2H), δ, DMSO-d ₆); 0.84 (t, J=7.2 Hz, 3H), 1.70-2.22(m, 10H), 4.37 (t, J=7.4 Hz, 2H), 7.27-7.32 (m, 1H), 7.50-7.59 (m, 3H).ESI MS; 380 (M⁺+1). m.p.; 198-200° C.

EXAMPLE 1701-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.87 (t, J=7.2 Hz, 3H), δ, DMSO-d₆); 0.87 (t,J=7.2 Hz, 3H), 1.79-2.01 (m, 4H), 2.33-2.42 (m, 2H), 2.46 (s, 1H),2.62-2.71 (m, 2H), 4.38 (t, J=7.4 Hz, 2H), 4.38 (t, J=7.4 Hz, 2H),7.29-7.34 (m, 1H), 7.50-7.60 (m, 3H). ESI MS; 366 (M⁺+1). m.p.; 144-146°C.

EXAMPLE 1714-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.72 (t, J=18.0 Hz, 3H), 1.58-1.69 (m, 2H),4.24 (q, J=18.0 Hz, 2H), δ, DMSO-d ₆); 0.72 (t, J=18.0 Hz, 3H),1.58-1.69 (m, 2H), 4.24 (q, J=18.0 Hz, 2H), 7.43-7.49 (m, 1H), 7.61-7.70(m, 3H). ESI MS; 354.1 (M⁺+1). m.p.; 167-168° C.

EXAMPLE 1721-{2-[2-6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.68 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.68(t, J=7.2 Hz, 3H), 1.55-1.81 (m, 6H), 1.89-1.98 (m, 4H), 4.02 (t, J=7.2Hz, 2H), 4.02 (t, J=7.2 Hz, 2H), 7.50-7.57 (m, 2H), 7.59-7.68 (m, 1H).ESI MS; 398.2 (M⁺+1). m.p.; 232-234° C.

EXAMPLE 1731-{2-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.68 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.68(t, J=7.2 Hz, 3H), 1.56-1.68 (m, 2H), 1.72-1.86 (m, 2H), 2.16-2.28 (m,2H), 2.32-2.46 (m, 2H), 4.03 (t, J=7.2 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H),7.52-7.58 (m, 2H), 7.60-7.70 (m, 1H). ESI MS; 384.2 (M⁺+1). m.p.;225-226° C.

EXAMPLE 1741-{2-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); 1.22 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.22(t, I=7.2 Hz, 3H), 1.72-1.87 (m, 2H), 2.17-2.27 (m, 2H), 2.34-2.43 (m,2H), 4.07 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H), 7.51-7.59 (m, 2H),7.59-7.67 (m, 1H). EST MS; 370 (M⁺+1). m.p.; 141-143° C.

EXAMPLE 1751-{2-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol

NMR (400 MHz, δ, d₆-DMSO); 1.22 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.22(t, J=7.2 Hz, 3H), 1.62-1.82 (m, 4H), 1.82-1.99 (m, 4H), 4.07 (q, J=7.2Hz, 2H), 4.07 (q, J=7.2 Hz, 2H), 7.48-7.58 (m, 2H), 7.58-7.66 (m, 1H).EST MS; 384 (M⁺+1). m.p.; 191-194° C.

EXAMPLE 1764-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol

NMR (400 MHz, δ, d₆-DMSO); 1.22 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.22(t, J=7.2 Hz, 3H), 1.48 (s, 6H), 4.07 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.2Hz, 2H), 7.49-7.58 (m, 2H), 7.58-7.66 (m, 1H). ESI MS; 358 (M⁺+1). m.p.;215-218° C.

EXAMPLE 1771-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol

NMR (400 MHz, δ, d₆-DMSO); 1.00 (t, J=7.2 Hz, 6H), 1.22 (t, J=7.2 Hz,3H), δ, DMSO-d ₆); 1.00 (t, J=7.2 Hz, 6H), 1.22 (t, J=7.2 Hz, 3H),1.58-1.73 (m, 4H), 4.07 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H),7.50-7.59 (m, 2H), 7.58-7.65 (m, 1H). ESI MS; 386 (M⁺+1). m.p.; 163-166°C.

EXAMPLE 1784-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.68 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.68(t, J=7.2 Hz, 3H), 1.48 (s, 6H), 1.55-1.68 (m, 2H), 4.03 (t, J=7.2 Hz,2H), 4.03 (t, J=7.2 Hz, 3H), 7.51-7.58 (m, 2H), 7.60-7.68 (m, 1H). ESIMS; 372.1 (M⁺+1). m.p.; 194-196° C.

EXAMPLE 1791-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.67 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.6 Hz,6H), 1.55-1.74 (m, 6H), 4.03 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.67 (t,J=7.2 Hz, 3H), 1.00 (t, J=7.6 Hz, 6H), 1.55-1.74 (m, 6H), 4.03 (t, J=7.2Hz, 3H), 7.51-7.58 (m, 2H), 7.60-7.67 (m, 1H). ESI MS; 400.2 (M⁺+1).m.p.; 164-165° C.

EXAMPLE 1802-[6-Amino-8-(3-fluorophenyl)-2[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]aceticAcid Hydrochloride

To 137 mg of ethyl2-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}acetateof Example 47 were added 1 ml of ethanol and 2 ml of a 1N aqueoussolution of sodium hydroxide and the mixture was stirred for 30 minutesat room temperature. After the reaction solution was concentrated, theresulting residue was dissolved in water and the solution was adjustedto pH 2 with a 1N aqueous solutoin of HCl. The resulting crystals werecollected by filtration and washed with water and ether to give 231 mgof the title compound. The yield was 65%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.20-1.30 (m, 1H), 1.41-1.67(m, 7H), 1.78-1.86 (m, 2H), 7.38-7.43 (m, 1H), 7.52-7.64 (m, 3H). FABMS; 410 (M⁺+1).

EXAMPLE 1813-[6-Amino-2-{2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}benzoicAcid Hydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.19-1.31 (m, 1H), 1.42-1.68(m, 7H), 1.80-1.89 (m, 2H), 3.82 (s, 3H), 7.71 (t, J=7.7 Hz, 1H),8.09-8.14 (m, 2H), 8.45 (d, J=1.3 Hz, 1H). 7.71 (t, J=7.7 Hz, 1H),8.09-8.14 (m, 2H), 8.45 (d, J=1.3 Hz, 1H). FAB MS; 392 (M⁺+1).

EXAMPLE 1825-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-4-pentynoic AcidHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.66-1.82 (m, 4H), 1.87-2.00(m, 4H), 3.86 (s, 3H), 7.43-7.50 (m, 1H), 7.63-7.70 (m, 1H), 7.71-7.77(m, 2H). FAB MS; 340 (M⁺+1).

EXAMPLE 183 (E)3-{4-{6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}phenyl}-2-propenoicAcid Hydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.21-1.33 (m, 1H), 1.42-1.69(m, 7H), 1.78-1.89 (m, 2H), 3.81 (s, 3H), 5.54 (br s, 1H), 6.66 (d,J=16.0 Hz, 1H), 7.47 (br s, 2H), 7.68 (d, J=16.0 Hz, 1H), 6.66 (d,J=16.0 Hz, 1H), 7.47 (br s, 2H), 7.68 (d, J−16.0 Hz, 1H), 7.84-7.98 (m,4H), 12.5 (br s, 1H). FAB MS; 418 (M⁺+1).

EXAMPLE 1842-{{8-(3-Fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-6-purinyl}amino}aceticAcid Hydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.21-1.32 (m, 1H), 1.41-1.68(m, 7H), 1.78-1.88 (m, 2H), 3.79 (s, 3H), 5.57 (s, 2H), 7.39-7.44 (m,1H), 7.59-7.65 (m, 1H), 7.69-7.73 (m, 2H), 8.09-8.12 (m, 1H). FAB MS;424 (M⁺+1).

EXAMPLE 1852-[3-(Dimethylamino)-1-propynyl]-8-(3-fluorophenyl)-9-methyl-9H-6-purinamineDihydrochloride

6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (200 mg) wasreacted with an ammonia-saturated methanol at 70° C. for 30 minutes in asealed tube. The reaction mixture was evaporated and then filtered togive 138 mg of 8-(3-fluorophenyl)-2-iodo-9-methyl-9H-6-purinamine.

NMR (400 MHz, δ, δ, CDCl₃); 3.84 (s, 3H), 5.76 (br s, 2H), 7.20-7.30 (m,H), 7.42-7.54 (m, 3H).

After that, a solution of 50 mg of8-(3-fluorophenyl)-2-iodo-9-methyl-9H-6-purinamine previously obtained,10 mg of dichlorobis(triphenylphosphine)palladium (II), 3 mg of copper(I) iodide, 22 ml of 1-dimethylamino-2-propyne and 28 ml oftriethylamine in 2 ml of DMF was stirred in nitrogen atmosphere at 80°C. for 20 minutes. Since the reaction was slow, 66 ml of1-dimethylamino-2-propyne were further added and the mixture was stirredat 80° C. for 1 hour more. The solvent was evaporated and the resultingresidue was diluted with chloroform. After blowing hydrogen sulfide forabout 20 seconds thereinto, a saturated aqueous solution of EDTA wasadded thereto and the mixture was neutralized with sodium carbonate andextracted with chloroform. The organic layer was dried over magnesiumsulfate, purified by a silica column chromatography (5%methanol/dichloromethane) and converted into a hydrochloride by a commonmethod to give 16 mg of the title compound.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 2.85 (s, 6H), 3.80 (s, 3H),4.35 (s, 2H), 7.39-7.96 (m, 1H), 7.60-7.72 (m, 31H). FAB MS; 325 (M⁺+1).

The compounds of Examples 186-201 were prepared similarly using thecorresponding 6-chloro-2-iodo compounds where a chlorine group atposition 6 was firstly converted to an amino group and then an iodinegroup at position 2 was converted to the corresponding ethynyl group.

EXAMPLE 1861-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-1-one

NMR (400 MHz, δ, δ, CDCl₃); 1.18 (d, J=6.3,6H), (d, J=6.3,6H), 2.66-2.80(m, 1H), 4.08 (s, 3H), 5.64 (br, 2H), 6.64 (dd, J=2.0 Hz,0.9 Hz, 1H),7.15 (d, J=2.0, 1H), 6.64 (dd, J=2.0 Hz,0.9 Hz, 1H), 7.15 (d, J=2.0,1H), 7.68 (m, 1H).

EXAMPLE 1873-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-1-phenyl-2-propyn-1-one

NMR (400 MHz, δ, δ, CDCl₃); 4.10 (s, 3H), 5.66 (br, 2H), 6.66 (dd, J=1.8Hz, 3.7 Hz, 1H), 7.18 (d, J=3.7, 1H), 6.66 (dd, J=1.8 Hz, 3.7 Hz, 1H),7.18 (d, J=3.7, 1H), 7.44-7.50 (m, 3H), 7.69 (m, 1H), 8.04-8.10 (m, 2H).

EXAMPLE 188N¹-Isopropyl-3-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-propynamide

NMR (400 MHz, δ, d₆-DMSO); 1.10 (d, J=6.0 Hz, 6H), δ, DMSO-d ₆); 1.10(d, J=6.0 Hz, 6H), 3.80 (s, 3H), 3.86-3.98 (m, 1H), 7.38-7.45 (m, 1H),7.58-7.74 (m, 3H), 8.90 (d, J=7.7 Hz, 1H). 8.90 (d, J=7.7 Hz, 1H). FABMS; 353 (M⁺+1).

EXAMPLE 189N¹-Cyclohexyl-8-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-propynamide

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.02-1.30 (m, 5H), 1.50-1.60(m, 1H), 1.64-1.80 (m, 4H), 3.54-3.64 (m, 1H), 3.80 (s, 3H), 7.39-7.45(m, 1H), 7.58-7.74 (m, 3H), 8.91 (d, J=8.2 Hz, 1H). 8.91 (d, J=8.2 Hz,1H).

EXAMPLE 190N¹-Phenyl-3-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-propynamide

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.80 (s, 3H), 7.08-7.12 (m,1H), 7.30-7.36 (m, 2H), 7.39-7.45 (m, 1H), 7.60-7.74 (m, 5H), 11.10 (s,1H). FAB MS; 387 (M⁺+1).

EXAMPLE 1913-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-purinyl]-1-piperidino-2-propyn-1-one

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.42-1.64 (m, 6H), 3.50 (br,2H), 3.72 (br, 2H), 3.80 (s, 3H), 7.40-7.45 (m, 1H), 7.60-7.78 (m, 3H).FAB MS; 379 (M⁺+1).

EXAMPLE 1923-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-morpholino-2-propyn-1-one

NMR (400 MHz, δ, d₆-DMSO); 3.66 (t, J=4.1 Hz, 2H), 3.74 (t, J=4.1 Hz,2H), δ, DMSO-d ₆); 3.66 (t, J=4.1 Hz, 2H), 3.74 (t, J=4.1 Hz, 2H), 3.80(s, 3H), 7.38-7.45 (m, 1H), 7.60-7.74 (m, 3H).

EXAMPLE 1932-[2-[4-Aminophenyl]-1-ethynyl]-8-(3-fluorophenyl)-9-methyl-9H-2-purinamineDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 3.10 (s, 3H), 6.69-6.78 (br s,2H), 7.34-7.40 (m, 2H), 7.41-7.47 (m, 1H), 7.60-7.74 (m, 5H). FAB MS;359 (M⁺+1).

EXAMPLE 194N-[3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2-propyl]methanesulfonamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62 (s, 6H), 3.19 (s, 3H),3.83 (s, 3H), 7.40-7.47 (m, 1H), 7.60-7.66 (m, 2H), 7.67-7.75 (m, 2H).FAB MS; 403 (M⁺+1).

EXAMPLE 195Ethyl-N-{3-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2-propyl}carbamateHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.18 (t, J=7.0 Hz, 3H), δ, DMSO-d ₆); 1.18(t, J=7.0 Hz, 3H), 1.56 (s, 6H), 3.80 (s, 3H), 4.00 (q, J=7.0 Hz, 2H),4.00 (q, J=7.0 Hz, 2H), 7.39-7.45 (m, 1H), 7.49 (br s, 2H), 7.54 (br s,1H), 7.59-7.66 (m, 1H), 7.78-7.74 (m, 2H). FAB MS; 397 (M⁺+1).

EXAMPLE 1964-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-phenyl-3-buten-2-ol

NMR (400 MHz, δ, δ, CDCl₃); 1.93 (s, 3H), 2.86 (br s, 1H), 3.90 (s, 3H),5.72 (br s, 2H), 7.21-7.29 (m, 1H), 7.29-7.33 (m, 1H), 7.35-7.41 (m,2H), 7.47-7.57 (m, 3H), 7.73-7.78 (m, 2H).

EXAMPLE 1973-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(2-methoxyphenyl)-2-propyn-1-ol

NMR (400 MHz, δ, δ, CDCl₃); 3.48 (s, 1H), 3.88 (s, 3H), 3.92 (s, 3H),5.95 (br s, 2H), 6.91-6.94 (m, 1H), 6.96-7.01 (m, 1H), 7.21-7.26 (m,1H), 7.28-7.34 (m, 1H), 7.46-7.56 (m, 3H), 7.62-7.66 (m, 1H).

EXAMPLE 1984-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-(3-pyridyl)-3-butyn-2-ol

NMR (400 MHz, δ, δ, CDCl₃); 1.93 (s, 3H), 3.87 (s, 3H), 6.20 (br-s, 2H),7.20-7.37 (m, 2H), 7.42-7.57 (m, 3H), 8.01-8.09 (m, 1H). ESI MS; 389(M⁺+1).

EXAMPLE 1993-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(3-methoxy)-2-propyn-1-ol

NMR (400 MHz, δ, δ, CDCl₃); 3.83 (s, 3H), 3.88 (s, 3H), 5.71 (br-s, 1H),5.92 (br, 2H), 6.85-6.90 (m, 1H), 7.16-7.33 (m, 4H), 7.45-7.56 (m, 3H).

EXAMPLE 2003-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(4-methoxyphenyl)-2-propyn-1-ol

NMR (400 MHz, δ, δ, CDCl₃); 3.80 (s, 3H), 3.86 (s, 3H), 5.68 (br-s, 1H),6.28 (br s, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),7.20-7.26 (m, 1H), 7.43-7.56 (m, 5H).

EXAMPLE 2014-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-(4-pyridinyl)-3-butyn-2-ol

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.74 (s, 3H), 3.80 (s, 3H),6.63 (s, 1H), 7.38-7.46 (m, 1H), 7.48-7.76 (m, 7H), 8.61 (br, 2H).

EXAMPLE 202N¹-Ethyl-4-[6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl-1-ethylnyl)-9H-9-purinyl]butaneamideHydrochloride

1) 4-[6-Amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoic Acid

To 1.50 g of 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanolwere added 30 ml of chloroform, 30 ml of acetonitrile, 45 ml of water,73 mg of ruthenium tetraoxide hydrate and4.10 g of sodium periodate andthe mixture was vigorously stirred in a nitrogen stream for 5 hours atroom temperature. The reaction was stopped by 2-propanol and theinsoluble matters were filtered off followed by washing with 1000 ml ofchloroform-methanol (1:1). The filtrate was concentrated, the residuewas suspended in water, and the suspension was adjusted to pH 2-3 with1N hydrochloric acid and the crystals were collected by filtration. Thecrystals were washed with water and ether to give 1.41 g of the titlecompound. The yield was 91%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.76-1.94 (m, 2H), 2.13 (t,J=7.0 Hz, 2H), 4.20 (t, J=7.2 Hz, 2H), 2.13 (t, J=7.0 Hz, 2H), 4.20 (t,J=7.2 Hz, 2H), 7.36-7.47 (m, 1H), 7.54-7.68 (m, 3H), 7.74 (br s, 2H).

2) Methyl 4-[6-amino-8-(3-fluorophenyl)-2-iodod-9H-9-purinyl]butanoate

Thionyl chloride (1.2 ml) was added dropwise into a mixture of 1.41 g of4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoid acid and 75ml of methanol over 15 minutes during the mixutre was stirred at 0-5° C.in a nitrogen stream. This was raised to room temperature and stirredfor 45 minutes and the solvent was evaporated. The resulting residue wasdissolved in ethyl acetate and then the solutionw as washed with asaturated aqueous solution of sodium bicarbonate twice and then withbrine once. The orgnaic layer was dried over anhydrous sodium sulfateand concentrated to give 1.45 g of the title compound. The yield was100%.

3) Methyl4-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl}butanoate]

To 162 mg of methyl4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoate were added 8ml of N,N-dimethylformamide, 30 mg of copper(I) iodide, 30 mg ofdichlorobis(triphenylphosphine)palladium(II)l, 80 mg of1-ethylcyclohexanol and 74 μl of triethylamine and the mixutre wasstirred in a nitrogen stream at 70° C. for 2.5 hours. After it wasallowed to cool, the solvent was evaporated and the resulting reside wassubjected to a silica gel column chromatography (25 g of silica gel;chloroform-methanol (100:0-100:1-50:1) to give 144 mg of the titlecompound. The yield was 90%.

4N¹-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]butanoateHydrochloride

To 663 mg of methyl4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl-9H-9-purinyl]butanoatewere added 20 ml of a 70% aqueous solution of ethylamine and the mixturewas stirred in a sealed tube at 80° C. for 5 hours. The reactionsolution was cooled to room temperature and the solvent wasconcentrated. The resulting resiude was subjected to a silica gel columnchromatography (25 g of silica gel; dichloromethane-methanol(100:0-100:1-50:1-40:1-30:1-20:1) to give 439 mg of a crude product.This was suspended in ethyl acetate, collected by fitlration and washedwith ethyl acetate and ether to give 396 mg of the desired freecompound. This was converted into a hydrochloride by a conventionalmethod to give 400 mg of the title compound. The yield was 54%.

NMR (400 MHz, δ, d₆-DMSO); 0.91 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.91(t, J=7.2 Hz, 3H), 1.20-1.32 (m, 1H), 1.40-1.67 (m, 7H), 1.78-1.87 (m,4H), 1.93 (t, J=7.1 Hz, 2H), 2.94 (dq, J=5.5,7.2 Hz, 2H), 4.25 (t, J=7.1Hz, 2H), 1.93 (t, J=7.1 Hz, 2H), 2.94 (dq, J=5.5,7.2 Hz, 2H), 4.25 (t,J=7.1 Hz, 2H), 7.40-7.45 (m, 1H), 7.58-7.65 (m, 3H), 7.72 (t, J=5.5 Hz,1H). 7.72 (t, J=5.5 Hz, 1H). FAB MS (m/z); 465 (M⁺+1).

Similarly were prepared the compounds of Examples 69 and 204.

EXAMPLE 203N¹-Ethyl-4-[amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]acetamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.96 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.96(t, J=7.2 Hz, 3H), 1.18-1.31 (m, 1H), 1.41-1.67 (m, 7H), 1.78-1.90 (m,2H), 3.06 (dq, J=5.5,7.2 Hz, 2H), 3.06 (dq, J=5.5,7.2 Hz, 2H), 4.84 (s,2H), 7.38-7.44 (m, 1H), 7.52-7.63 (m, 3H), 8.40 (t, J=5.5 Hz, 1H). 8.40(t, J=5.5 Hz, 1H). FAB MS; 437 (M⁺+1).

EXAMPLE 2044-[6-Amino-9-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.19-1.33 (m, 1H), 1.40-1.70(m, 9H), 1.79-1.91 (m, 4H), 1.97 (t, J=7.3 Hz, 2H), 4.25 (t, J=7.4 Hz,2H), 1.97 (t, J=7.3 Hz, 2H), 4.25 (t, J=7.4 Hz, 2H), 6.74 (br s, 1H),7.24 (br s, 1H), 7.40-7.46 (m, 1H), 7.59-7.68 (m, 3H). FAB MS; 437(M⁺+1).

EXAMPLE 205N¹-Phenyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-purinyl]butaneamideHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.18-1.32 (m, 1H), 1.40-1.68(m, 7H), 1.79-1.88 (m, 2H), 1.90-2.01 (m, 2H), 2.21 (t, J=7.2 Hz, 2H),4.32 (t, J=7.2 Hz, 2H), 6.98 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.6 Hz, 2H),7.34-7.41 (m, 1H), 7.46 (d, J=7.6 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 4.32(t, J=7.2 Hz, 2H), 6.98 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.6 Hz, 2H)5 ,7.34-7.41 (m, 1H), 7.46 (d, J=7.6 Hz, 2H), 7.54-7.59 (m, 1H), 7.64-7.67(m, 2H), 9.82 (s, 1H). FAB MS; 513 (M⁺+1).

EXAMPLE 2061-{2-[8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol

A methanesulfonate (470 mg) prepared from1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanolby a conventional method was dissolved in 25 ml of tetrahydrofuran, 0.44ml of isoamyl nitride was added thereto and the mixture was heated underreflux for 1 hour. The reaction solution was concentrated to dryness andpurified by a silica gel column (eluting withdichloromethane:methanol=95:5) to give 20 mg of the title compound.

NMR (400 MHz, δ, δ, CDCl₃); 1.26-1.39 (m, 1H), 1.50-1.82 (m, 7H),2.04-2.15 (m, 2H), 7.26-7.33 (m, 1H), 7.50-7.65 (m, 3H), 9.08 (s, 1H).FAB MS; 351 (M⁺+1).

EXAMPLE 2078-(3-fluorophenyl)-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9-methyl-9H-6-purinol

To 50 mg of1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanolwere added 3.0 ml of allyl alcohol and 1.0 ml of 5M NaOH, the mixturewas stirred at room temperature for 10 minutes, 1.0 ml of THF was addedthereto and the mixture was stirred again at room temperature for 15hours and 40 minutes. The solvent was evaporated and then 200 ml ofethyl acetate and water (1:1) were added and an extraction was carriedout. The aqueous lyaer was extracted with 100 ml of ethyl acetate againand the all organic layers were combined and washed with water and withbrine once each. The organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated. The resulting residue waspurified by a p-TLC (CH₂Cl₂:MeOH=10:1), the resulting yellowish whitecrystals were suspended in diethyl ether and the suspenion was filteredto give 217 mg of the title compound as white crystals. The yield was36%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.68-1.81 (m, 4H), 1.92-2.00(m, 4H), 3.82 (s, 3H), 5.62 (s, 1H) 7.39-7.43 (m, 1H), 7.60-7.71 (m,3H), 12.86 (s, 1H).

EXAMPLE 2081-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl}-1-cyclopentanolHydrochloride

A solution of 500 mg of1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cyclopentanolin 5 ml of tetrahydrofuran was added dropwise into a solution of 170 mgof lithium aluminum hydride in 10 ml of tetrahydrofuran at a temperaturelower than 7° C. in a nitrogen atmosphere, followed by stirring for 30minutes. Water (0.2 ml), 0.2 ml of 5N sodium hydroxide and 0.6 ml ofwater were added dropwise into the reaction mixture was ice-cooling tostop the reaction. The insoluble matters were filtered off, washed withethyl acetate and the filtrate was concentrated. The resulting residuewas subjected to a silica gel column chromatography (20 g of silica gel;dichloromethane-dichloromethane:methanol=40:1-20:1) and then to the same(20 g of NH silica gel;dichloromethane-dichloromethane:methanol=150:1-100:1-40:1) to give 160mg of a free substance of 3. The resulting free compound was dissolvedin methanol, five drops of 5N hydrochloric acid were added and themixture was concentrated. The resulting residue was suspended in etherand the crystals were collected by filtration and washed with ether togive 108 mg of the title compound. The yield was 19%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.64-1.92 (m, 8H), 3.90 (s,3H), 6.70 (d, J=15.6 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 7.46-7.52 (m,1H), 7.51 (d, J=15.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.65-7.71 (m,1H), 7.73-7.80 (m, 2H). ESI MS; 354. m.p.; >290° C.

Similarly were prepared the compounds of Examples 209-212 using thecorresponding materials.

EXAMPLE 2091-[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethenyl]-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.31 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.31(t, J=7.2 Hz, 3H), 1.72-1.85 (m, 2H), 2.15-2.30 (m, 4H), 4.38 (q, J=7.2Hz, 2H), 6.64 (d, J=15.6 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 6.64 (d,J=15.6 Hz, 1H), 7.47-7.53 (m, 1H), 7.64-7.74 (m, 4H). ESI MS; 354. m.p.;178-180° C.

EXAMPLE 210(E)-4-[6-Amino--9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.30 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.30(t, J=7.2 Hz, 3H), 1.32 (s, 6H), 4.36 (q, J=7.2 Hz, 2H), 6.62 (d, J=15.6Hz, 1H), 7.38 (d, J=15.6 Hz, 1H) 4.36 (q, J=7.2 Hz, 2H), 6.62 (d, J=15.6Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 7.46-7.53 (m, 1H), 7.61-7.72 (m, 3H).ESI MS; 342.

EXAMPLE 211(E)-4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.32 (s, 6H), 3.90 (s, 3H),6.62 (d, J=16.0 Hz, 1H), 6.44 (d, J=16.0 Hz, 1H), 6.62 (d, J=16.0 Hz,1H), 6.44 (d, J=16.0 Hz, 1H), 7.45-7.52 (m, 1H), 7.65-7.72 (m, 1H),7.73-7.79 (m, 2H). ESI MS: 328. m.p.; >290° C.

EXAMPLE 212(E)-1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-ethyl-3-pente-1-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.85 (t, J=7.2 Hz, 6H), 1.59 (q, J=7.2Hz,4H), δ, DMSO-d ₆); 0.85 (t, J=7.2 Hz, 6H), 1.59 (q, J=7.2 Hz,4H),3.90 (s, 3H), 6.62 (d, J=15.6 Hz, 1H), 7.32 (d, J=15.6 Hz, 1H), 6.62 (d,J=15.6 Hz, 1H), 7.32 (d, J=15.6 Hz, 1H), 7.45-7.52 (m, 1H), 7.64-7.71(m, 1H), 7.72-7.79 (m, 2H). ESI MS; 356;

EXAMPLE 213 1-[(E) and(Z)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolHydrochloride

1) 1-[(E) and (Z)-2-(1,1,1-Tributylstannyl)-1-ethenyl]-1-cyclopentanols

A mixture of 10 g of 1-ethynyl-1-cyclopentanol, 30 ml of tributyl inhydride and 190 mg of azobis (isobutyronitrile) was stirred in anitrogen atmosphere at 90° C. for 3 hours. The reaction mixture wasevaporated to give 27 g of a mixture of E- and Z-substances (E:Z=15:1)of b.p. 135° C. (0.2 mmHg).

NMR (400 MHz, CDCl₃)δ; δ, CDCl₃); 0.80-0.98 (m, 9H), 1.25-1.92 (m, 26H),5.86 (d, J=13.2 Hz, 5.86 (d, J=13.2 Hz, ═CHSn of Z isomer), 6.14 (s, 2H,HC═CH of E isomer), 6.61 (d, J=13.2 Hz, 6.61 (d, J=13.2 Hz, ═CH of Zisomer).

2)-1-[(E) and(Z)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolHydrochloride

The above prepared mixture (17.93 g) of 1-[(E) and(Z)-2-(1,1,1-tributylstannyl)-1-ethynyl]-1-cyclopentanols, 11 g of8-(3-fluorophenyl)-2-iodod-9-methyl-9H-6-purinamine, 8.25 g oftetrabutylammonium chloride and 671 mg of palladium acetate weresuspended in 165 ml of toluene and the suspension was stirred in anitrogen atmosphere at 90° C. for 3.5 hours. The reaction mixture wasdiluted with 165 ml of ethyl acetate and washed with a saturatedammonium chloride solution and brine. The organic layer was dried overanhydrous magneisum sulfate and then concentrated. The resulting residuewas subjected to a silica gel column chromatography (350 g of silicagel; hexane, hexane:ethyl acetate (4:1, 1:1, 1:2 and 1:4) and ethylacetate) and then the resulting crystals were washed with ethylacetate/hexane to give 6.6 g of crude1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanol.This was suspended in 70 ml of methanol, dissolved by addition of 7 mlof 5N hydrochloric acid and the solution was concentrated. Aftersuspending with ether/ethyl acetate, the crystals were collected byfiltration, washed with ether and air-dried at 60° C. for 10 hours togive 5.92 g (51% yield) of1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolhydrochloride which was the same as that obtained in Example 208. NMRand MS were the same as those mentioned above.

The filtrate was concentrated and re-purified to give 450 mg (4% yield)of1-[(Z)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolhydrochloride.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.62-1.88 (m, 6H), 1.90-2.03(m, 2H), 3.86 (s, 3H), 6.35 (d, J=13.2 Hz, 1H), 6.44 (d, J=13.2 Hz, 1H),6.35 (d, J=13.2 Hz, 1H), 6.44 (d, J=13.2 Hz, 1H), 7.44-7.52 (m, 1H),7.64-7.72 (m, 1H), 7.72-7.78 (m, 2H). ESI MS; 354.

Similarly were synthesized the compounds of Examples 214 to 227.

EXAMPLE 2141[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.30 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.30(t, J=7.2 Hz, 3H), 1.64-1.90 (m, 8H), 4.36 (q, J=7.2 Hz, 2H), 6.69 (d,J=15.6 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 6.69(d, J=15.6 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H), 7.47-7.53 (m, 1H),7.65-7.71 (m, 3H). ESI MS; 368.

EXAMPLE 2151-[(E)-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.73-1.84 (m, 2H), 2.14-2.32(m, 4H), 3.92 (s, 3H), 6.64 (d, J=16.0 Hz, 1H), 6.64 (d, J=16.0 Hz, 1H),7.46-7.52 (m, 1H), 7.65-7.72 (m, 1H), 7.73 (d, J=16.0 Hz, 1H), 7.73 (d,J−16.0 Hz, 1H), 7.74-7.80 (m, 2H). ESI MS; 340. m.p.; 181-184° C.

EXAMPLE 2161-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.22-1.36 (m, 1H), 1.46-1.74(m, 9H), 3.90 (s, 3H), 6.65 (d, J=15.6 Hz, 1H), 7.44-7.52 (m, 1H), 7.48(d, J=15.6 Hz, 1H), 6.65 (d, J=15.6 Hz, 1H), 7.44-7.52 (m, 1H), 7.48 (d,J=15.6 Hz, 1H), 7.64-7.71 (m, 1H), 7.73-7.79 (m, 2H). ESI MS; 368. m.p.;222-225° C.

EXAMPLE 2171-[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl]-1-cyclohexanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.31 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.31(t, J=7.2 Hz, 3H), 1.47-1.72 (m, 10H), 4.37 (q, J=7.2 Hz, 2H), 6.65 (d,J=16.0 Hz, 1H), 7.47-7.54 (m, 1H), 7.59 (d, J=16.0 Hz, 1H), 4.37 (q,J=7.2 Hz, 2H), 6.65 (d, J=16.0 Hz, 1H), 7.47-7.54 (m, 1H), 7.59 (d,J=16.0 Hz, 1H), 7.65-7.72 (m, 3H). ESI MS; 382.

EXAMPLE 218(E)-1-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-3-ethyl-3-penten-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.85 (t, J=7.2 Hz, 6H), 1.30 (t, J=7.2 Hz,3H), 1.58 (q, J=7.2 Hz,4H), 4.36 (q, J=7.2 Hz, 2H), 6.62 (d, J=16.0 Hz,1H), 7.30 (d, J=16.0 Hz, 1H), δ, DMSO-d ₆); 0.85 (t, J=7.2 Hz, 6H), 1.30(t, J=7.2 Hz, 3H), 1.58 (q, J=7.2 Hz,4H), 4.36 (q, J=7.2 Hz, 2H), 6.62(d, J=16.0 Hz, 1H), 7.30 (d, J=16.0 Hz, 1H), 7.47-7.53 (m, 1H),7.64-7.72 (m, 3H ). ESI MS; 370.

EXAMPLE 219(E)-4-[6-Amino-8-(3-fluorophenyl)-9-phenyl-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.26 (s, 6H), 6.50 (d, J=16.0Hz, 1H), 7.19 (d, J=16.0 Hz, 1H), 6.50 (d, J=16.0 Hz, 1H), 7.19 (d,J=16.0 Hz, 1H), 7.22-7.35 (m, 3H), 7.42-7.51 (m, 3H), 7.56-7.62 (m, 3H).ESI MS; 390.

EXAMPLE 2201-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.74 (t, J=7.2 Hz, 3H), 1.66 (sex, J=7.2 Hz,2H), δ, DMSO-d ₆); 0.74 (t, J=7.2 Hz, 3H), 1.66 (sex, J=7.2 Hz, 2H),1.71-1.85 (m, 2H), 2.14-2.30 (m, 4H), 4.33 (t, J=7.2 Hz, 2H), 6.64 (d,J=16.0 Hz, 1H), 4.33 (t, J=7.2 Hz, 2H), 6.64 (d, J=16.0 Hz, 1H),7.46-7.53 (m, 1H), 7.64-7.74 (m, 4H). ESI MS; 368.

EXAMPLE 2211-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.74 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.74(t, J=7.2 Hz, 3H), 1.60-1.93 (m, 10H), 4.32 (t, J=7.2 Hz, 2H), 6.69 (d,J=15.6 Hz, 1H), 4.32 (t, J=7.2 Hz, 2H), 6.69 (d, J=15.6 Hz, 1H),7.46-7.54 (m, 1H), 7.50 (d, J=15.6 Hz, 1H), 7.50 (d, J=15.6 Hz, 1H),7.64-7.72 (m, 3H). ESI MS; 382.

EXAMPLE 2221-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.74 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.74(t, J=7.2 Hz, 3H), 1.23-1.37 (m, 1H), 1.47-1.60 (m, 9H), 1.66 (sex, 2H),4.32 (t, J=7.2 Hz, 2H), 6.65 (d, J=16.0 Hz, 1H), 7.46-7.52 (m, 1H), 7.54(d, J=16.0 Hz, 1H), 4.32 (t, J=7.2 Hz, 2H), 6.65 (d, J=16.0 Hz, 1H),7.46-7.52 (m, 1H), 7.54 (d, J=16.0 Hz, 1H), 7.66-7.72 (m, 3H). ESI MS;396.

EXAMPLE 223(E)-4-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.74 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.74(t, J=7.2 Hz, 3H), 1.32 (s, 6H), 1.66 (sex, J=7.2 Hz, 2H), 4.33 (t,J=7.2 Hz, 2H), 6.62 (d, J=15.6 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 1.66(sex, J=7.2 Hz, 2H), 4.33 (t, J=7.2 Hz, 2H), 6.62 (d, J=15.6 Hz, 1H),7.43 (d, J=15.6 Hz, 1H), 7.46-7.53 (m, 1H), 7.65-7.72 (m, 3H). ESI MS;356.

EXAMPLE 224(E)-1-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-3-penten-3-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.73 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz,6H), 1.58 (q, J=7.2 Hz,4H), 1.66 (sex, J=7.2 Hz, 2H), 4.32 (t, J=7.2 Hz,2H), 6.61 (d, J=15.6 Hz, 1H), 7.29 (d, J=15.6 Hz, 1H), δ, DMSO-d ₆);0.73 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 6H), 1.58 (q, J=7.2 Hz,4H),1.66 (sex, J=7.2 Hz, 2H), 4.32 (t, J=7.2 Hz, 2H), 6.61 (d, J=15.6 Hz,1H), 7.29 (d, J=15.6 Hz, 1H), 7.45-7.52 (m, 1H), 7.64-7.72 (m, 3H ). ESIMS; 384.

EXAMPLE 2251-[(E)-2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl]-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.77-0.84 (m, 2H), 1.08-1.16(m, 2H), 1.72-1.86 (m, 2H), 2.14-2.32 (m, 4H), 3.78-3.84 (m, 1H), 6.64(d, J=15.6 Hz, 1H), 6.64 (d, J=15.6 Hz, 1H), 7.44-7.51 (m, 1H),7.62-7.70 (m, 1H), 7.70 (d, J=15.6 Hz, 1H), 7.70 (d, J=15.6 Hz, 1H),7.81-7.89 (m, 2H). ESI MS; 366.

EXAMPLE 2261-[(E)-2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl-1-ethenyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.77-0.83 (m, 2H), 1.07-1.14(m, 2H), 1.65-1.93 (m, 8H), 3.80 (sept, J=3.6 Hz, 1H), 6.70 (d, J=15.6Hz, 1H), 7.44-7.50 (m, 1H), 7.50 (d, J=15.6 Hz, 1H), 3.80 (sept, J=3.6Hz, 1H), 6.70 (d, J=15.6 Hz, 1H), 7.44-7.50 (m, 1H), 7.50 (d, J=15.6 Hz,1H), 7.63-7.70 (m, 1H), 7.81-7.88 (m, 2H). ESI MS; 380.

EXAMPLE 227(E)-4-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 0.77-0.84 (m, 2H), 1.07-1.55(m, 2H), 1.33 (s, 6H), 3.80 (sept, J=3.6 Hz, 1H), 6.63 (d, J=16.0 Hz,1H), 7.41 (d, J=16.0 Hz, 1H), 3.80 (sept, J=3.6 Hz, 1H), 6.63 (d, J=16.0Hz, 1H), 7.41 (d, J=16.0 Hz, 1H), 7.44-7.51 (m, 1H), 7.62-7.70 (m, 1H),7.80-7.88 (m, 2H). ESI MS; 354.

EXAMPLE 228(Z)-4-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-olHydrochloride

To a solution of 200 mg of4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-olin 20 ml of methanol were added 5 μl of quinoline and 20 mg of 10%palladium/barium carbonate and the mixture was stirred in a hydrogenatmosphere at room temperature for 10 minutes. The palladium/bariumcarbonate was filtered off and the filtrate was concentrated and thenthe resulting residue was subjected to a silica gel columnchromatography (15 g of silica gel;dichloromethane-dichloromethane/methanol=60:1-40:1) to give(Z)-4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-ol.This was dissolved in methanol and five drops of 5N hydrochloric acidwere added thereto followed by concentrating. Ethyl acetate and etherwere added to the resulting residue and the crystals were collected byfiltration and washed with ether to give 851 mg of the product. Theyield was 26%.

NMR (400 MHz, δ, d₆-DMSO); 1.33 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.33(t, J=7.2 Hz, 3H), 1.45 (s, 6H), 4.31 (q, J=7.2 Hz, 2H), 6.33 (d, J=13.4Hz, 1H), 6.40 (d, J=13.4 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 6.33 (d,J=13.4 Hz, 1H), 6.40 (d, J=13.4 Hz, 1H), 7.47-7.54 (m, 1H), 7.64-7.72(m, 3H). ESI MS; 342.

EXAMPLE 2291-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopentanolHydrochloride

To a solution of 300 mg of1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cyclopentanolin 20 ml of methanol were added six drops of 5N hydrochloric acid and 63mg of 10% palladium/carbon and the mixture was stirred in a hydrogenatmosphere at room temperature for 17 hours. The palladium/carbon wasfiltered off, the filtrate was concentrated and the residue wasdissolved in ethyl acetate and saturated sodium hydrogen carbonate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. The resulting residue was subjected to a silica gelcolumn chromatography (15 g of silica gel; dichloromethane,dichloromethane/methanol (40:1, 20:1 and 10:1) to give1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopentanol.This was dissolved in methanol and then five drops of 5N hydrochloricacid were added thereto followed by concentrating. Ether was added tothe residue and the crystals were collected by filtration and washedwith ether to give 6209 209 mg of the product. The yield was 69%.

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.45-1.80 (m, 8H), 2.02 (t,J=8.0 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 2.02 (t, J=8.0 Hz, 2H), 3.00 (t,J=8.0 Hz, 2H), 3.88 (s, 3H), 7.45-7.52 (m, 1H), 7.64-7.71 (m, 1H),7.72-7.78 (m, 2H). ESI MS; 356.

Similarly were synthesized the compounds of Examples 230 to 237.

EXAMPLE 2301-[2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.45-1.58 (m, 1H), 1.60-1.70(m, 1H), 2.00 (dd, J=6.8 and 8.8 Hz, 4H), 2.06 (t, J=8.0 Hz, 2H), 2.93(t, J=8.0 Hz, 2H), 2.00 (dd, J=6.8 and 8.8 Hz, 4H), 2.06 (t, J=8.0 Hz,2H), 2.93 (t, J=8.0 Hz, 2H), 3.89 (s, 3H), 7.45-7.52 (m, 1H), 7.64-7.71(m, 1H), 7.72-7.78 (m, 2H). ESI MS; 342.

EXAMPLE 2311-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-3-pentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.84 (t, J=7.2 Hz, 6H), 1.42 (q, J=7.2 Hz,4H), δ, DMSO-d ₆); 0.84 (t, J=7.2 Hz, 6H), 1.42 (q, J=7.2 Hz, 4H),1.82-1.92 (m, 2H), 2.84-2.94 (m, 2H), 3.88 (s, 3H), 7.45-7.52 (m, 1H),7.64-7.71 (m, 1H), 7.72-7.77 (m, 2H). ESI MS; 358.

EXAMPLE 2321-[2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethyl]-1-cyclobutanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.29 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 1.29(t, J=7.2 Hz, 3H), 1.44-1.57 (m, 1H), 1.58-1.72 (m, 1H), 1.99 (dd, J=6.8and 8.8 Hz, 4H), 2.05 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz, 2H), 4.34(q, J=7.2 Hz, 2H), 1.99 (dd, J=6.8 and 8.8 Hz, 4H), 2.05 (t, J=8.0 Hz,2H), 2.93 (t, J=8.0 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 7.47-7.53 (m, 1H),7.64-7.72 (m, 3H). ESI MS; 356.

EXAMPLE 2331-[2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-purinyl]-1-ethyl]-1-cyclopentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 1.29 (t, J=7.2 Hz, 3H), 1.42-1.81 (m, 8H),2.03 (t, J=8.0 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H),δ, DMSO-d ₆); 1.29 (t, J=7.2 Hz, 3H), 1.42-1.81 (m, 8H), 2.03 (t, J=8.0Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 7.47-7.53 (m,1H), 7.63-7.72 (m, 3H). ESI MS; 370.

EXAMPLE 2344-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-2-butanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.17 (s, 6H), 1.29 (t, J=7.2Hz, 3H), 1.91 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 4.33 (q, J=7.2Hz, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.91 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.47-7.53 (m, 1H), 7.64-7.72 (m, 3H).ESI MS; 344.

EXAMPLE 2351-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9-2-purinyl]-3-ethyl]-3-pentanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.83 (t, J=7.2 Hz, 6H), 1.30 (t, J=7.2 Hz,3H), 1.42 (q, J=7.2 Hz, 4H), δ, DMSO-d ₆); 0.83 (t, J=7.2 Hz, 6H), 1.30(t, J=7.2 Hz, 3H), 1.42 (q, J=7.2 Hz, 4H), 1.83-1.92 (m, 2H), 2.84-2.95(m, 2H), 4.34 (q, J=7.2 Hz, 2H), 4.34 (q, J=7.2 Hz, 2H), 7.47-7.53 (m,1H), 7.64-7.72 (m, 3H). ESI MS; 372.

EXAMPLE 2364-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]2-methyl-2-butanolHydrochloride

NMR (400 MHz, δ, d₆-DMSO); 0.72 (t, J=7.2 Hz, 3H), δ, DMSO-d ₆); 0.72(t, J=7.2 Hz, 3H), 1.17 (s, 6H), 1.64 (sex, J=7.2 Hz, 3H), 1.91 (t,J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 4.30 (t, J=7.2 Hz, 2H), 1.64(sex, J=7.2 Hz, 3H), 1.91 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H),4.30 (t, J=7.2 Hz, 2H), 7.46-7.53 (m, 1H), 7.64-7.72 (m, 3H). ESI MS;358.

EXAMPLE 2374-[6-Amino-9-[4-(dimethylamino)phenyl]-8-(3-fluoro-phenyl)-9H-2-purinyl]-2-methyl-2-butanolDihydrochloride

NMR (400 MHz, δ, d₆-DMSO); δ, DMSO-d ₆); 1.12 (s, 6H), 1.76-1.82 (m,2H), 2.82-2.90 (m, 2H), 3.00 (s, 6H), 6.89 (d, J=8.8 Hz, 2H), 7.25 (d,J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.27-7.37(m, 3H), 7.44-7.51 (m, 1H). ESI MS; 435.

Structural formulae of the compounds of the above Examples are shown inTable 3.

TABLE 3 Ex. No. Structural Formula 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213-1

213-2

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

Next, in order to facilitate the understanding that the adenosine A2receptor antagonist has an antidiabetic action, several examples wherethe fundamental skeletons are different in chemical structures will beshown as hereunder. It goes without saying that the present invention isnot limited thereto.

EXAMPLE 238 Adenosine A1 Receptor Binding Experiment

Human adenosine A1 receptor cDNA was subjected to an over-expression inCHOK1 cells and its membrane specimen was suspended in an incubationbuffer (20 mM HEPES, 10 mM MgCl₂ and 100 mM NaCl; pH 7.4) to make theconcentration 66.7 μg/ml. To 0.45 ml of this membrane specimen wereadded 0.025 ml of tritium-labeled chlorocyclopentyl adenosine (60 nM³H-CCPA; 30 Ci/mmol) and 0.025 ml of the compound to be tested. Thesolution of the compound to be tested was prepared in such a mannerthat, firstly, the compound was dissolved in DMSO to make 20 mMconcentration and then successively diluted each 10-fold using anincubation buffer. The mixture was allowed to stand at 30° C. for 120minutes, subjected to a quick suction on a glass fiber filter (GF/B;manufactured by Whatman) and immediately washed with 5 ml of ice-cooled50mM Tris-HCl buffer twice. After that, the glass fiber filter wastransferred to a vial bottle, a scintillator was added and theradioactivity on the filter was measured by a liquid scintillationcounter. Calculation of the inhibition rate of the test compound to thereceptor bond (³H-CCPA) was carried out by the following expression and,based upon that, IC₅₀ was calculated.Inhibition Rate (%)=[1−{(Binding amount in the presence ofdrug-Non-specific binding amount)/(Total binding amount-Non-specificbinding amount)}]×100

Total binding amount is a ³H-CCPA binding radioactivity in the absenceof the test compound.

Non-specific binding amount is a ³H-CCPA binding radioactivity in thepresence of 100 μM of RPIA.

Binding amount in the presence of drug is a ³H-CCPA bindingradioactivity in the presence of the test compound of variousconcentrations.

The inhibition constant (Ki value) in Table was calculated fromCheng-Prusoff's expression.

The results are shown in Table 4.

EXAMPLE 239 Adenosine A2a Receptor Binding Experiment

A membrane specimen prepared by an over-expression of adenosine A2areceptor was purchased from Receptor Biology, Inc. and adenosine A2areceptor binding experiments were carried out using that. The purchasedmembrane specimen was suspended in an incubation buffer (20 mM HEPES, 10mM MgCl₂ and 100 mM NaCl; pH 7.4) to make the concentration 22.2 μg/ml.To 0.45 ml of this membrane specimen were added 0.025 ml oftritium-labeled ³H-CGS21680 (500 nM; 30 Ci/mmol) and 0.025 ml of thetest compound. The solution of the test compound was prepared in such amanner that, firstly, the compound was dissolved in DMSO to make 20 mMconcentration and then successively diluted each 10-fold using anincubation buffer. The mixture was allowed to stand at 25° C. for 90minutes, subjected to a quick suction on a glass fiber filter (GF/B;manufactured by Whatman) and immediately washed with 5 ml of ice-cooled50 mM Tris-HCl buffer twice. After that, the glass fiber filter wastransferred to a vial bottle, a scintillator was added and theradioactivity on the filter was measured by a liquid scintillationcounter. Calculation of the inhibition rate of the test compound to thereceptor bond (³H-CGS21680) of A2a was carried out by the followingexpression and, based upon that, IC₅₀ was calculated.Inhibition Rate (%)=[1−{(Binding amount in the presence ofdrug-Non-specific binding amount)/(Total binding amountamount-Non-specific binding amount)}]×100

Total binding amount is a ³H-CGS21680 binding radioactivity in theabsence of the test compound.

Non-specific binding amount is a ³H-CGS21680 binding radioactivity inthe presence of 100 μM of RPIA.

Binding amount in the presence of drug is a ³H-CGS21680 bindingradioactivity in the presence of the test compound of variousconcentrations.

The inhibition constant (Ki value) in Table was calculated fromCheng-Prusoff's expression.

The results are shown in Table 4.

TABLE 4 Human adenosine A1, A2a receptor binding test A1 receptor A2areceptor Receptor Test Compound Ki (μM) Ki (μM)

0.024 0.002

0.019 0.0014

0.054 0.75

10< 0.052

10< 0.047

EXAMPLE 240 Evaluation of Test Compound in Adenosine A2b ReceptorExpressed Cells Using Suppression of NECA-stimulated cAMP Expression asan Index

Human adenosine A2b receptor cDNA was over-expressed in CHOK1 cells. Thecells were uniformly placed on a 24-well plate at the rate of 1.5×10⁵cells/well, incubated for one night and then used for the experiments.Affinity of the test compound to the A2b receptor was evaluated in whichthe index used was the degree of suppression of the amount of cAMPproduced by stimulation of NECA (30 nM) which was an adenosine agonistin the presence of the test compound. Thus, after washing with 2 ml/wellof an incubation buffer (Krebs solution; pH7.4) twice, a pre-incubationwas carried out at 0.5 ml/well for 30 minutes. After that, 100 μl/wellof a mixed solution containing 600 μM of Ro-20-1724 (phosphodiesteraseinhibitor), 180 nM of NECA and a test compound which was 6-foldconcentrated in a reaction solution were added. After 15 minutes, thereaction was stopped by substituting 0.1N HCl (300 μl/well) for thereaction solution. Measurement of cAMP was carried out using an AmershamcAMP EIA Kit.

Calculation of the suppression rate of the test compound to theNECA-stimulated cAMP production was done by the following expression.Inhibition Rate (%)=[1−{(cAMP amount in the presence of NECA and testcompound-cAMP amount in the case of incubation buffer only)/(cAMP amountstimulated only by NECA-cAMP amount in the case of incubation bufferonly)}]×100.

IC₅₀ (3-fluorophenyl) was calculated from the above.

The result is shown in Table 5.

TABLE 5 suppressing action to NECA-stimulated cAMP production inadenosine A2b receptor expressed cells Receptor A2b receptor CompoundIC₅₀ (μM) Compound A 0.028 Compound B 0.070 Compound C 0.10 KW6002 2.85KF17837 1.36

EXAMPLE 241 Action of Spontaneous Diabetic Mice (KK-A^(y)/Ta Jcl) toHyperglycemia (by Single Administration)

-   -   Animals: Five male KK-A^(y)/TA Jcl mice for each group        (introduced from Nippon Clair)    -   Preparation and Administration of Test Compound: A test compound        in a dose shown in Table 6 was suspended in a 0.5% aqueous        solution of methyl cellulose and was orally administered in a        dose at a volume of 10 ml/kg.    -   Collection of Blood Samples and Determination of Blood Sugar        Glucose: Blood was collected from tail vein immediately before        administration of the test compound and also five hours after        the administration and blood sugar glucose was determined.    -   Method: Tail vein of mouse was injured by a razor without an        anesthetization to bleed slightly. The blood (15 μl) was        collected and immediately mixed with 135 μl of a 0.6 M        perchloric acid. Glucose in the supernatant obtained by a        centrifugal separation (at 1500 g for 10 minutes at 4° C. using        a cooling centrifuge GS-6KR of Beckmann) was determined by a        Glucose CII Test Wako (Wako Pure Chemicals).

The result is shown in Tables 6-1 to 6-4 for each experiment.

The result is shown in terms of “(% ratio of the blood sugar after 5hours from the administration to the blood sugar before theadministration)±(standard error)”. The data were subjected to a one-waylayout analysis of variance and then subjected to a multiple comparisonof Dunnett type. The case where p<0.05 was judged that a significantdifference was available.

TABLE 6-1 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 72.4 ± 4.4 Compound 1047.8 ± 4.8 ** A Compound 10 51.8 ± 2.9 ** B Compounds A and B areadministered in a form of sulfate. (**; p < 0.01 vs. Solvent)

TABLE 6-2 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 69.8 ± 2.3 Compound 3048.5 ± 3.4 ** C (**; p < 0.01 vs. Solvent)

TABLE 6-3 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 76.6 ± 3.9 KW6002 10057.6 ± 5.6 * (*; p < 0.05 vs. Solvent)

TABLE 6-4 Action of spontaneous diabetic mice (KK-A⁷/Ta Jcl) tohyperglycemia Test Compound Dose (mg/kg) $\frac{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{5\quad{hr}\quad{after}\quad{the}\quad{administration}}\end{matrix}}{\begin{matrix}{{Blood}\quad{sugar}\quad{level}} \\{{before}\quad{the}\quad{administration}}\end{matrix}} \times 100$ Sig- nificance Solvent 80.7 ± 2.3 KF17837 10062.0 ± 2.8 * (*; p < 0.05 vs. Solvent)

As such, adenosine A2 receptor antagonist showed a clear hypoglycemicaction in spontaneous diabetic models.

In the experiments for the NECA-stimulated glucose production in hepaticcells, the antagonist which was specific to adenosine A2a receptor didnot show a saccharogenesis glucose production suppressing action andonly the compound showing a strong suppressing action of A2b affinity toA2b receptor showed a saccharogenesis glucose production suppressingaction. In addition, a glucose tolerance improving action in glucosetolerance test which is an index for sugar glucose utilization inperipheral tissues was noted both in antagonists which were specific toadenosine A2a and in compounds having a strong antagonistic action toA2b receptor.

On the other hand, no hypoglycemic action was noted for FK453 (EuropeanJournal of Pharmacology, 279, 217-225, 1995.) known as an antagonistspecific to adenosine A1 receptor even at the dose of 100 mg/kg in thepresent diabetic models. In addition, no glucose tolerance improvingaction was noted in glucose tolerance test as well.

From the above, it is clear that the effect in the present diabeticmodels is due to an antagonistic action of adenosine A2 (A2a and/or A2b)receptor.

REFERENTIAL EXAMPLE Synthesis of2-(3-Fluorophenyl)-(4-pyridyl)-3H-imidazo[4,5-b]pyridine Hydrochloride(Compound C)

N²-(4-Pyridyl)-2,3-pyridinediamine was dissolved in 20 ml of methanol, 1ml of acetic acid and 745 mg of 3-fluorobenzaldehyde were added and themixture was stirred at room temperature for 16 hours. The reactionsolution was concentrated and subjected to an azeotropy with toluene forthree times. The resulting residue after concentration was suspended in30 ml of ethanol, 1.5 g of anhydrous iron chloride were added theretoand the mixture was heated under reflux for 5 hours. The reactionsolution was returned to room temperature, concentrated to dryness,diluted with 100 ml of ethyl acetate and washed with 50 ml of water and20 ml of brine. The organic layer was concentrated to dryness and theresidue was purified by a silica gel column chromatography (eluted withethyl acetate:n-hexane=3:1) to give 0.36 g of a free compound. The freecompound was dissolved in 20 ml of methanol, 6.5 ml of 1N hydrochloricacid were added thereto and the mixture was concentrated to dryness.Ethanol was added to the residue, the mixture was subjected to anazeotropy, suspended in 10 ml ethyl acetate and 0.45 g of the titlecompound was obtained by collecting by filtration. The overall yield was46%.

NMR (400 MHz, δ, δ, DMSO-d₆); 7.35-7.55 (m, 5H), 7.88 (d, J=6.4 Hz, 2H),8.33 (dd, J=1.6 Hz, 8.0 Hz, 1H), 8.45 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94(d, J=6.4 Hz, 2H). 7.88 (d, J=6.4 Hz, 2H), 8.33 (dd, J=1.6 Hz, 8.0 Hz,1H), 8.45 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94 (d, J=6.4 Hz, 2H).

The purine compound and the adenosine A2 receptor antagonists which arethe compounds of the present invention show a clear hypoglycemic actionin spontaneous diabetic models and also have an action of improving animpaired glucose tolerance, whereby they are useful as a preventive ortherapeutic agent for diabetes mellitus and diabetic complications.

1. A purine compound represented by the formula (I), or itspharmacologically acceptable salt thereof,

wherein in the formula (I), R¹ represents: 1) formula:

 wherein X is a hydrogen atom, a hydroxyl group, an optionallysubstituted lower alkyl group, an optionally substituted lower alkoxygroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group, an optionally substituted acyl group, an optionallysubstituted acyloxy group or an optionally substituted amino group; andR⁵ and R⁶ are the same as or different from each other and eachrepresents a hydrogen atom, an optionally substituted lower alkyl group,an optionally substituted saturated or unsaturated C₃₋₈ cycloalkylgroup, an optionally substituted C₃₋₈ cycloalkyl-C₂₋₆ alkyl group, anoptionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally protected carboxyl group or an optionallysubstituted four- to six-membered ring having at least one hetero atom;optionally R⁵ and R⁶ is either an oxygen atom or a sulfur atom together,or R⁵ and R⁶ are a ring which may have a hetero atom being formedtogether with a carbon atom to which they are bonded; wherein said ringmay be substituted; or 2) a five- or six-membered aromatic ring that mayhave a substituent group and a hetero atom; W represents formula—CH₂CH₂—, —CH═CH— or —C≡C—; R² represents a hydrogen atom, an optionallysubstituted lower alkyl group, a hydroxyl group or a formula —NR⁷R⁸,wherein R⁷ and R⁸ are the same as or different from each other and eachrepresents a hydrogen atom, a hydroxyl group, an optionally substitutedlower alkyl group, and optionally substituted acyl group, an optionallysubstituted C₃₋₈ cycloalkyl group, an optionally substituted aryl groupor an optionally substituted heteroaryl group; optionally R⁷ and R⁸ area saturated ring which is formed together with a nitrogen atom to whichthey are bonded, said saturated ring is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperidine,perhydroazepine, perhydroazocine, piperazine, homopiperazine, morpholineand thiomorpholine; wherein the ring optionally has a substituentselected from the group consisting of a lower alkyl group, a halogen andan acyl group; R³ represents an optionally substituted C₃₋₈ cycloalkylgroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group or an optionally substituted C₂₋₆ alkenyl group; and R⁴represents a hydrogen atom, an optionally substituted lower alkyl group,an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted aryl group, an optionally substituted heteroaryl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group or an optionally substituted cyclic ether group;wherein when W is —CH₂CH₂—, then X is not a hydrogen atom or an alkylgroup.
 2. The purine compound or its pharmacologically acceptable saltthereof as claimed in claim 1, wherein W is —C≡C—.
 3. The purinecompound, or its pharmacologically acceptable salt thereof, as claimedin claim 1 or 2, wherein R² is formula —NR⁷R⁸, and R⁷ and R⁸ have thesame meanings as defined above.
 4. The purine compound as claimed inclaim 1, or its pharmacologically acceptable salt thereof, wherein R³ isan optionally substituted aryl group or an optionally substitutedheteroaryl group.
 5. The purine compound as claimed in claim 1, or itspharmacologically acceptable salt thereof, wherein R⁴ is an optionallysubstituted lower alkyl group, an optionally substituted aryl group oran optionally substituted heteroaryl group.
 6. The purine compound asclaimed in claim 1, or its pharmacologically acceptable salt thereof,wherein R¹ is a formula:

wherein X represents a hydroxyl group, an acyloxy group or an optionallysubstituted lower alkyl group; and R⁵ and R⁶ are the same as ordifferent from and each represents an optionally substituted lower alkylgroup or a ring being formed together with the carbon atom to which theyare bonded which may have a hetero atom and may be substituted.
 7. Thepurine compound as claimed in claim 1, or its pharmacologicallyacceptable salt thereof, wherein R¹ is a formula:

wherein X represents a hydroxyl group or a lower aliphatic acyloxygroup; and R⁵ and R⁶ are the same as or different from each other andeach represents an optionally substituted lower alkyl group or anoptionally substituted C₃₋₈ cycloalkyl group being formed with thecarbon atom to which they are bonded; and R² is a formula —NR⁷R⁸,wherein R⁷ and R⁸ are the same as or different from and each representsa hydrogen atom, a lower alkyl group or an acyl group.
 8. The purinecompound as claimed in claim 1, or its pharmacologically acceptable saltthereof, wherein R¹ is a formula:

wherein X represents a hydroxyl group or a lower aliphatic acyloxygroup; and R⁵ and R⁶ are the same as or different from each other andeach represents an optionally substituted lower alkyl group or anoptionally substituted C₃₋₈ cycloalkyl group being formed together withthe carbon atom to which they are bonded; and R² is a formula —NR⁷R⁸,wherein both R⁷ and R⁸ represent hydrogen atoms.
 9. The purine compoundas claimed in claim 1, or its pharmacologically acceptable salt thereof,wherein R¹ is a formula:

wherein X represents a hydroxyl group or a lower aliphatic acyloxygroup; and R⁵ and R⁶ are the same as or different from and eachrepresents a linear or branched lower alkyl group or cyclobutyl group,cyclopentyl group or cyclohexyl group being formed together with thecarbon atom to which they are bonded, and the ring may be substitutedwith a hydroxyl group, a lower aliphatic acyloxy group, a linear orbranched lower alkyl group, a lower alkoxy group or a halogen atom; R²is a formula —NR⁷R⁸, wherein both R⁷ and R⁸ are hydrogen atoms; R³ is aphenyl group which may be substituted with hydroxyl group, a halogenatom, a linear or branched lower alkyl group, a lower alkoxy group, anacyl group, amino group, a mono- or di-lower alkylamino group or a cyanogroup; and R⁴ is a lower alkyl group which may be substituted with ahydroxyl group, a halogen atom, a cyano group, an amino group, a mono-or di-lower alkylamino group, a lower alkoxy group, a carbamoyl group, amono- or di-substituted carbamoyl group, a carboxyl group or a loweralkyloxycarboxyl group.
 10. The purine compound, or itspharmacologically acceptable salt thereof, as claimed in claim 1,wherein R¹ is a formula:

wherein X represents a hydroxyl group; and R⁵ and R⁶ are the same as ordifferent from and each represents a lower alkyl group or a cyclobutylgroup, a cyclopentyl group or a cyclohexyl group being formed with thecarbon atom to which they are bonded; R² is a formula —NR⁷R⁸, whereinboth R⁷ and R⁸ are hydrogen atoms; R³ is an optionallyhalogen-substituted phenyl group; and R⁴ is a lower alkyl group.
 11. Thepurine compound, or its pharmacologically acceptable salt thereof, asclaimed in claim 1 selected from the group consisting of: 1)1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;2)1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;3)1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;4)1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;5)1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;6)1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol;7)1-{2-[6-amino-9-dimethylaminophenyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol;8)1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol;9)1-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol;10)4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol;11)4-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol;12)4-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol;and 13)1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol.12. A 2,6-dihalo-substituted purine compound represented by the formula(II):

wherein A and B represent halogen atoms; R³ represents an optionallysubstituted C₃₋₈ cycloalkyl group, an optionally substituted aryl groupor an optionally substituted heteroaryl group; and R⁴ represents anoptionally substituted linear or branched lower alkyl group, anoptionally substituted aryl group or an optionally substitutedheteroaryl group.
 13. A method for the manufacturing of a6-amino-2-ethynylene compound represented by the formula (V):

wherein R³ represents an optionally substituted C₃₋₈ cycloalkyl group,an optionally substituted aryl group or an optionally substitutedheteroaryl group; R⁴ represents a linear or branched alkyl group, anoptionally substituted aryl group or an optionally substitutedheteroaryl group; R¹ represents: 1) formula:

 wherein X is a hydrogen atom, a hydroxyl group, an optionallysubstituted lower alkyl group, an optionally substituted lower alkoxygroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group, an optionally substituted acyl group, an optionallysubstituted acyloxy group or an optionally substituted amino group; andR⁵ and R⁶ are the same as or different from and each represents ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted cycloalkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, an optionallyprotected carboxyl group or an optionally substituted four- tosix-membered ring having at least one hetero atom; optionally, R⁵ and R⁶is either an oxygen atom or a sulfur atom together or are a ring whichmay have hetero atom being formed together with a carbon atom to whichthey are bonded; wherein the ring may be substituted; or 2) a five- orsix-membered aromatic ring which may have substituent group and hetero,to give a 2-ethynylene-6-halopurine compound represented by the formula(IV):

 wherein A is a halogen atom, and R¹, R³ and R⁴ have the same meaningsas defined above; and R²¹ and R²² are the same as or different from eachother and each represents a hydrogen atom or an optionally substitutedlower alkyl group or a saturated 3- or 8-membered ring being formedtogether with the nitrogen atom to which they are bonded and the ringcontaining said nitrogen atom optionally has another heteroatom ofnitrogen or oxygen or is substituted; comprising the steps of: a)reacting a 2,6-dihalo-substituted purine compound represented by theformula (II):

 wherein A and B represent halogen atoms, and R³ and R⁴ are defined asabove, with an ethynylene compound represented by the formula (III):R¹C═CH  (III)  wherein in the formula (III) R¹ is defined as above informula (V); and b) reacting the resulting compound with HNR²¹R²² toform said 6-amino-2-ethynylene compound represented by the formula (V).14. A method for the manufacture of a 6-amino-2-ethynylene compoundrepresented by the formula (V):

wherein R³ represents an optionally substituted C₃₋₈ cycloalkyl group,an optionally substituted aryl group or an optionally substitutedheteroaryl group; R⁴ represents a linear or branched alkyl group, anoptionally substituted aryl group or an optionally substitutedheteroaryl group; R¹ represents: 1) formula:

 wherein X is a hydrogen atom, a hydroxyl group, an optionallysubstituted lower alkyl group, an optionally substituted lower alkoxygroup, an optionally substituted aryl group, an optionally substitutedheteroaryl group, an optionally substituted acyl group, an optionallysubstituted acyloxy group or an optionally substituted amino group; andR⁵ and R⁶ are the same as or different from and each represents ahydrogen atom, an optionally substituted lower alkyl group, anoptionally substituted cycloalkyl group, an optionally substituted arylgroup, an optionally substituted heteroaryl group, an optionallyprotected carboxyl group or an optionally substituted four- tosix-membered ring having at least one hetero atom; optionally, R⁵ and R⁶is either an oxygen atom or a sulfur atom together or are a ring whichmay have hetero atom being formed together with a carbon atom to whichthey are bonded; wherein the ring may be substituted; or 2) a five- orsix-membered aromatic ring which may have substituent group and hetero,to give a 2-ethynylene-6-halopurine compound represented by the formula(IV):

 wherein A is a halogen atom, and R¹, R³ and R⁴ have the same meaningsas defined above; and R²¹ and R²² are the same as or different from eachother and each represents a hydrogen atom or an optionally substitutedlower alkyl group or a saturated 3- or 8-membered ring being formedtogether with the nitrogen atom to which they are bonded and the ringcontaining said nitrogen atom optionally has another heteroatom or issubstituted, comprising the steps of: a) reacting a2,6-dihalo-substituted purine compound represented by the formula (II):

 wherein A and B represent halogen atoms, and R³ and R⁴ are defined asabove, with ammonia or a primary or secondary amine to give a6-amino-2-halopurine compound represented by the formula (VI):

 wherein B, R³, R⁴, R²¹ and R²² have the same meanings as defined above;and b) reacting the resulting compound with an ethynylene compoundrepresented by the formula (III):R¹—C≡H  (III)  wherein R¹ has the same meaning as defined above.
 15. Apreventive or therapeutic composition comprising: the purine compound asclaimed in claim 1, or its pharmacologically acceptable salt thereof, asan active ingredient, and a pharmaceutically acceptable carrier.
 16. Amethod of treating a disease or condition selected from the groupconsisting of diabetes mellitus, diabetic complications, hypoglycemia,hyperglycemia, impaired glucose tolerance and obesity, said methodcomprising: administering an effective amount of the purine compound ofclaim 1 to a patient in need thereof.
 17. The method according to claim16, wherein said disease or condition is impaired glucose tolerance. 18.The method according to claim 16, wherein said disease or condition isobesity.
 19. The method according to claim 16, wherein said disease orcondition is hypoglycemia. hyperglycemia.
 20. The method according toclaim 16, wherein said disease or condition is diabetes mellitus. 21.The method according to claim 16, wherein said disease or condition isdiabetic complications.
 22. A method of potentiating insulinsensitivity, said method comprising administering an effective amount ofthe purine compound of claim 1 to a patient in need thereof.